Glycosidase inhibitors

ABSTRACT

Compounds of formula (I), wherein A, R, W, Q, n and m have the meaning according to the claims, can be employed, inter alia, for the treatment of tauopathies and Alzheimer&#39;s disease.

The present invention relates to a medicament comprising a compound offormula (I)

wherein A, R, W, Q, n and m have the meaning according to the claims,and/or physiologically acceptable salts, tautomers, solvates,stereoisomers and derivatives thereof. The compounds of formula (I) canbe used as glycosidase inhibitors. Objects of the invention are alsopharmaceutical compositions comprising the compounds of formula (I), andthe use of the compounds of formula (I) for the treatment of one or moretauopathies and Alzheimer's disease.

A wide range of cellular proteins, both nuclear and cytoplasmic, arepost-translationally modified by the addition of the monosaccharide2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetyl glucosamine) whichis attached via an O-glycosidic linkage. This modification is generallyreferred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzymeresponsible for post-translationally linking β-N-acetylglucosamine(GlcNAc) to specific serine and threonine residues of numerousnucleocytoplasmic proteins is O-GlcNAc transferase (OGTase). A secondenzyme, known as O-GlcNAcase, removes this post-translationalmodification to liberate proteins making the O-GlcNAc-modification adynamic cycle occurring several times during the lifetime of a protein.

O-GlcNAc-modified proteins regulate a wide range of vital cellularfunctions including, for example, transcription, proteasomal degradationand cellular signaling. O-GlcNAc is also found on many structuralproteins. For example, it has been found on a number of cytoskeletalproteins, including neurofilament proteins, synapsins, synapsin-specificclathrin assembly protein AP-3 and Ankyrin-G. O-GlcNAc modification hasbeen found to be abundant in the brain. It has also been found onproteins clearly implicated in the etiology of several diseasesincluding tauopathies, Alzheimer's disease (AD), synucleinopathies,Parkinson's disease, amyotrophic lateral sclerosis, and cancer.

For example, it is well established that AD and a number of relatedtauopathies including Down's Syndrome, progressive supranuclear palsy(PSP), Pick's disease, corticobasal degeneration (CBD), argyrophilicgrain disease (AGD), globular glial tauopathy (GGT), frontotemporaldementia and parkinsonism linked to chromosome-17 (FTLD-17, Niemann-PickType C disease are characterized, in part, by the development ofneurofibrillary tangles (NFTs). NFTs are also a histopathologicalhallmark of chronic traumatic encephalopathy that is a consequence oftraumatic brain injury. These NFTs are aggregates of paired helicalfilaments (PHFs) and are composed of an abnormal form of thecytoskeletal protein “tau”. Normally, tau stabilizes a key cellularnetwork of microtubules that is essential for distributing proteins andnutrients within neurons. In AD patients, however, tau becomeshyperphosphorylated, disrupting its normal function, forming PHFs andultimately aggregating to form NFTs. Six isoforms of tau are found inthe human brain. In AD patients, all six isoforms of tau are found inNFTs, and all are markedly hyperphosphorylated. Tau in healthy braintissue bears only 2 or 3 phosphate groups, whereas those found in thebrains of AD patients bear, on average, 8 phosphate groups. A clearparallel between NFT levels in the brains of AD patients and theseverity of dementia strongly supports a key role for tau dysfunction inAD. The precise causes of this hyperphosphorylation of tau remainelusive. Accordingly, considerable effort has been dedicated toward: a)elucidating the molecular physiological basis of tauhyperphosphorylation; and b) identifying strategies that could limit tauhyperphosphorylation in the hope that these might halt, or even reverse,the progression of tauopathies and Alzheimer's disease. Several lines ofevidence suggest that up-regulation of a number of kinases may beinvolved in hyperphosphorylation of tau, although very recently, analternative basis for this hyperphosphorylation has been advanced.

In particular, it has recently emerged that phosphate levels of tau areregulated by the levels of O-GlcNAc on tau. The presence of O-GlcNAc ontau has stimulated studies that correlate O-GlcNAc levels with tauphosphorylation levels. The recent interest in this field stems from theobservation that O-GlcNAc modification has been found to occur on manyproteins at amino acid residues that are also known to bephosphorylated. Consistent with this observation, it has been found thatincreases in phosphorylation levels result in decreased O-GlcNAc levelsand conversely, increased O-GlcNAc levels correlate with decreasedphosphorylation levels. This reciprocal relationship between O-GlcNAcand phosphorylation has been termed the “Yin-Yang hypothesis” and hasgained strong biochemical support by the recent discovery that theenzyme OGTase forms a functional complex with phosphatases that act toremove phosphate groups from proteins. Like phosphorylation, O-GlcNAc isa dynamic modification that can be removed and reinstalled several timesduring the lifespan of a protein. Suggestively, the gene encodingO-GlcNAcase has been mapped to a chromosomal locus that is linked to AD.Hyperphosphorylated tau in human AD brains has markedly lower levels ofO-GlcNAc than are found in healthy human brains. Very recently, it hasbeen shown that O-GlcNAc levels of soluble tau protein from human brainsaffected with AD are markedly lower than those from healthy brain.Furthermore, PHF from diseased brain was suggested to lack completelyany O-GlcNAc modification whatsoever. The molecular basis of thishypoglycosylation of tau is not known, although it may stem fromincreased activity of kinases and/or dysfunction of one of the enzymesinvolved in processing O-GlcNAc. Supporting this latter view, in bothPC-12 neuronal cells and in brain tissue sections from mice, anonselective N-acetylglucosaminidase inhibitor was used to increase tauO-GlcNAc levels, whereupon it was observed that phosphorylation levelsdecreased. Moreover, it has been described that the O-GlcNAcmodification of tau directly inhibits its aggregation without perturbingthe conformational properties of tau monomers. The implication of thesecollective results is that by maintaining healthy O-GlcNAc levels in ADpatients, such as by inhibiting the action of O-GlcNAcase (OGA), oneshould be able to block hyperphosphorylation of tau and all of theassociated effects of tau hyperphosphorylation, including the formationof NFTs and downstream effects. However, because the proper functioningof the lysosomal β-hexosaminidases is critical, any potentialtherapeutic intervention for the treatment of AD that blocks the actionof O-GlcNAcase would have to avoid the concomitant inhibition of bothlysosomal hexosaminidases A and B.

Consistent with the known properties of the hexosamine biosyntheticpathway, the enzymatic properties of O-GlcNAc transferase (OGTase), andthe reciprocal relationship between O-GlcNAc and phosphorylation, it hasbeen shown that decreased glucose availability in brain leads to tauhyperphosphorylation. The gradual impairment of glucose transport andmetabolism leads to decreased O-GlcNAc and hyperphosphorylation of tau(and other proteins). Accordingly, the inhibition of O-GlcNAcase shouldcompensate for the age-related impairment of glucose metabolism withinthe brains of health individuals as well as patients suffering from ADor related neurodegenerative diseases.

These results suggest that a malfunction in the mechanisms regulatingtau O-GlcNAc levels may be vitally important in the formation of NFTsand associated neurodegeneration. Good support for blocking tauhyperphosphorylation as a therapeutically useful intervention comes fromstudies showing that when transgenic mice harboring human tau aretreated with kinase inhibitors, they do not develop typical motordefects and, in another case, show a decreased level of insoluble tau.These studies provide a clear link between lowering tau phosphorylationlevels and alleviating AD-like behavioral symptoms in a murine model ofthis disease.

There is evidence indicating that the modification with O-GlcNAc mayhave a general function in preventing harmful protein aggregation. Thishas been directly demonstrated for the tau protein and also for theprotein alpha-synuclein that is a toxic aggregating protein associatedwith synucleinopathies, including Parkinson's disease. Two otheraggregating proteins that are associated with amyotrophic lateralysclerosis (Tar DNA binding protein-43 (TDP-43) and superoxide-dismutaseI (SOD-I)) and frontotemporal lobar degeneration (TDP-43) are known tocarry the O-GlcNAc modification. These results indicate that increasingO-GlcNAcylation with OGA inhibitors could be in general beneficial indiseases associated with protein aggregation.

There is also a large body of evidence indicating that increased levelsof O-GlcNAc protein modification provides protection against pathogeniceffects of stress in cardiac tissue, including stress caused byischemia, hemorrhage, hypervolemic shock, and calcium paradox. Forexample, activation of the hexosamine biosynthetic pathway (HBP) byadministration of glucosamine has been demonstrated to exert aprotective effect in animal models of ischemia/reperfusion, traumahemorrhage, hypervolemic shock and calcium paradox. Moreover, strongevidence indicates that these cardioprotective effects are mediated byelevated levels of protein O-GlcNAc modification. There is also evidencethat the O-GlcNAc modification plays a role in a variety ofneurodegenerative diseases, including Parkinson's disease and relatedsynucleinopathies, and Huntington's disease.

Humans have three genes encoding enzymes that cleave terminalβ-N-acetyl-glucosamine residues from glycoconjugates. The first of theseencodes the enzymeO-glycoprotein-2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase).O-GlcNAcase is a member of family 84 of glycoside hydrolases.O-GlcNAcase acts to hydrolyze O-GlcNAc off of serine and threonineresidues of post-translationally modified proteins. Consistent with thepresence of O-GlcNAc on many intracellular proteins, the enzymeO-GlcNAcase appears to have a role in the etiology of several diseasesincluding type II diabetes, AD and cancer. Although O-GlcNAcase waslikely isolated earlier on, about 20 years elapsed before itsbiochemical role in acting to cleave O-GlcNAc from serine and threonineresidues of proteins was understood. More recently O-GlcNAcase has beencloned, partially characterized, and suggested to have additionalactivity as a histone acetyltransferase.

However, a major challenge in developing inhibitors for blocking thefunction of mammalian glycosidases, including O-GlcNAcase, is the largenumber of functionally related enzymes present in tissues of highereukaryotes. Accordingly, the use of non-selective inhibitors in studyingthe cellular and organismal physiological role of one particular enzymeis complicated because complex phenotypes arise from the concomitantinhibition of such functionally related enzymes. In the case ofβ-N-acetylglucosaminidases, existing compounds that act to blockO-GlcNAcase function are non-specific and act potently to inhibit thelysosomal β-hexosaminidases. Low molecular weight OGA inhibitors aree.g. disclosed in the international applications WO 2008/025170 and WO2014/032187. However, no OGA inhibitor has reached the market yet. Thus,there is still a need for low molecular weight molecules thatselectively inhibit OGA.

U.S. Pat. No. 3,489,757. mentions i.a. the following compounds:

(1-[1-(1,3-benzodioxol-5-yl)ethyl]-4-(4-methyl-2-thiazolyl)-piperazineand2-(4-(1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)ethyl)piperazin-1-yl)-4-methylthiazole).

U.S. Pat. No. 3,485,757 teaches the respective compounds for thetreatment of hypertension and does not relate to the use in thetreatment neurodegenerative diseases, diabetes, cancer, cardiovasculardiseases and stroke or to OGA inhibitor activity.

U.S. Pat. No. 3,299,067 discloses compounds as medicaments, inparticular as peripheral vasodilators, analgesics and anti-inflammatoryagents. U.S. Pat. No. 3,299,067 does not disclose any OGA inhibitoractivity. The compounds of U.S. Pat. No. 3,299,067 bear a methylenegroup in the bridging position. U.S. Pat. No. 3,299,067 does not referto any OGA inhibitor activity.

WO 99/21850 discloses compounds that bind to the dopamine D4 receptorsubtype and are said to be useful in treatment of variousneuropsychological disorders. However, the compounds are not active asOGA inhibitors. For example, compound 5 of WO 99/21850 shows thefollowing data, when measured according to Example B01 of the presentapplication (Human O-GlcNAcase enzyme inhibition assay):

Compounds that modulate MCH binding to MCH receptors are presented in WO2005/110982. The compounds are said to be useful in the treatment ofeating disorders, sexual disorders, diabetes, heart disease, and stroke,which are unrelated to the indications of the present invention. Thecompounds are not active as OGA inhibitors. For instance, the compoundof example 72 of WO 2005/110982 provides the following data, whenmeasured according to Example B01 of the present application:

WO 2009/053373 discloses molecules for the treatment of PARP-mediateddisorders, such as neurodegenerative diseases. The molecules of WO2009/053373 are not useful as OGA inhibitors. For instance, the compoundof example 56 of WO 99/21850 shows the following data, when measuredaccording to Example B01 of the present application:

The present invention has the object of finding novel compounds havingvaluable properties, in particular those which can be used for thepreparation of medicaments.

It has been surprisingly found that the compounds according to theinvention and salts thereof have very valuable pharmacologicalproperties. In particular, they act as glycosidase inhibitors. Theinvention relates to compounds of formula (I)

wherein

-   R is straight chain or branched alkyl having 1 to 6 carbon atoms,    wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH.    Preferably R is methyl, CH₂OH, CF₃, CHF₂, CH₂F;-   W is CH or N, preferably N;-   A denotes one of the following groups:

-   X is N or CR^(′″). Preferably all or one or two of X in a group are    CH;-   X¹, X² is N or CR^(′″);-   X³ is N or CR′″″-   X⁴ is N or CR⁹;-   R⁹ denotes Hal, NR³R⁴, CHR³R⁴, OR³, CN, straight chain or branched    alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH₂-groups may be    replaced by a group selected from O, NR³, S, SO, SO₂, S(O)(NH), CO,    COO, OCO, CONR³, NR³CO and wherein 1 to 5 hydrogen atoms may be    replaced by Hal, NR³R⁴ or NO₂;-   Y is O, S, SO or SO₂. Preferably Y is O or S;-   R^(′), R^(″) denote each independently H, Hal or straight chain or    branched alkyl having 1 to 12 carbon atoms. Preferably both are    either H, F or methyl;-   R^(′″), R^(″″) independently denote H, Hal, NR³R⁴, CHR³R⁴, OR³, CN,    straight chain or branched alkyl having 1 to 12 carbon atoms,    wherein 1 to 3 CH₂-groups may be replaced by a group selected from    O, NR³, S, SO, SO₂, S(O)(NH), CO, COO, OCO, CONR³, NR³CO and wherein    1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴ or NO₂.    Preferably both R″ and/or R″ are H, Hal, NR³R⁴, CHR³R⁴, OR³, CN or    alkyl;-   R′″″ denotes H, Hal, NR³R⁴, CHR³R⁴, CN, straight chain or branched    alkyl having 1 to 12 carbon atoms, wherein 1 to 3 CH₂-groups may be    replaced by a group selected from O, NR³, S, SO, SO₂, S(O)(NH), CO,    COO, OCO, CONR³, NR³CO and wherein 1 to 5 hydrogen atoms may be    replaced by Hal, NR³R⁴ or NO₂. Preferably, R is H, Hal or alkyl;-   R³, R⁴ denote each independently H or a straight chain or branched    alkyl group having 1 to 12 carbon atoms, preferably H, methyl or    ethyl;-   Q denotes one of the following groups:

-   Z², denotes CR⁵, CR⁶ or N; Z⁴ is N, CH, CON, COCH;-   Z⁵ is S, O, NR⁸, SO₂, CHR⁵, preferably NH, NCH₃, NCOCH₃, NSO₂CH₃,    CHSO₂CH₃ or CHNHSO₂CH₃;-   Z^(5′) is S, O, NR⁸, SO₂;-   Z⁶ is CH₂, CO;-   s denotes 0 or 1;-   T is N, CH or CR⁷;-   R³′ denotes H or a straight chain or branched alkyl group having 1    to 12 carbon atoms, wherein 1 to 3 CH₂-groups may be replaced by a    group selected from SO₂, CO, O and wherein 1 to 5 hydrogen atoms may    be replaced by Hal;-   R³″ denotes a straight chain or branched alkyl group having 1 to 12    carbon atoms, wherein 1 to 3 CH₂-groups are replaced by a group    selected from SO₂, CO, O and wherein 1 to 5 hydrogen atoms may be    replaced by Hal;-   R⁵, R⁶, R⁷ independently denote H, Hal, NR³R⁴, NO₂, straight chain    or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3    CH₂-groups may be replaced by a group selected from O, NR³, S, SO,    SO₂, S(O)(NH), CO, COO, OCO, CONR³, NR³CO and wherein 1 to 5    hydrogen atoms may be replaced by Hal, NR³R⁴, NO₂, OR³, Het, Ar,    Cyc, or denote Ar, Het or Cyc, R⁵, R⁶, R⁷ independently also denote    preferably OH;-   R⁸ denotes H, methyl or straight chain or branched alkyl having 2 to    12 carbon atoms, wherein 1 to 3 CH₂-groups may be replaced by a    group selected from O, NR³, S, SO, SO₂, CO, COO, OCO, CONR³, NR³CO    and wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴ or    NO₂;-   Hal denotes F, Cl, Br or I, preferably F, Cl or Br;-   Het denotes a saturated, unsaturated or aromatic ring, being    monocyclic or bicyclic or fused-bicyclic and having 3- to 8-members    and containing 1 to 4 heteroatoms selected from N, O and S, which    may be substituted by 1 to 3 substituents selected from R⁵, Hal and    OR³;-   Ar denotes a 6-membered carbocyclic aromatic ring or a fused or    non-fused bicylic aromatic ring system, which is optionally    substituted by 1 to 3 substituents independently selected from R⁵,    OR³ and Hal;-   Cyc denotes a saturated or an unsaturated carbocyclic ring having    from 3 to 8 carbon atoms which is optionally substituted by 1 to 3    substituents independently selected from R⁵ or Hal or OH;-   m and n denote independently from one another 0, 1, 2 or 3    and pharmaceutically usable derivatives, solvates, salts, prodrugs,    tautomers, enantiomers, racemates and stereoisomers thereof,    including mixtures thereof in all ratios and compounds of formula I,    wherein one or more H atoms are replaced by D (deuterium).

Specifically, formula (I) includes the following two enantiomers offormula Ia and Ib:

wherein A, R, W, Q, n and m have the meaning given above.

The invention also relates to a mixture of, i.e. a compositioncomprising, compounds Ia and Ib as set out above, having identicalgroups A, R, W, Q, n and m, in equal or unequal amounts.

Throughout the specification, R in formula I, Ia and Ib is preferablymethyl. The indices m and n in formula I, Ia and Ib are preferablysimultaneously 1.

Most preferably, compounds of formula I are the compounds of formula Aand B:

If individual groups, such as T, occurs more than once in a compound offormula I, it can have the same or different meanings according to therespective definition of that group.

Preferred compounds of the present invention are preferably used intheir non-racemic form, i.e. as enantiomerically pure compounds or theirenaniomerically enriched mixtures of the enantiomers. If R is anunsubstituted straight chain or branched alkyl having 1 to 6 carbonatoms, such as methyl, ethyl, n-propyl or iso-butyl, the S-entantiomersof compounds of formula I are preferred. Very preferred are formulae Iband B.

In general, compounds of formula I are preferred that contain one oremore preferred groups such as R′ to R′″″ or R³ to R⁷ or indices such asm or n. Compounds of formula I are the more preferred, the morepreferred groups or indices they contain.

If substituents, such as the group R⁸, are connected to the remainder ofthe molecule through a heteroatom, the connecting atom in the respectivegroup is preferably a carbon atom or the respective group is H.

The invention also relates to the use of compounds of formula (I) as amedicament.

In the meaning of the present invention, the compound is defined toinclude pharmaceutically usable derivatives, solvates, prodrugs,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds. The term “solvates” of the compounds istaken to mean adductions of inert solvent molecules onto the compounds,which are formed owing to their mutual attractive force. Solvates are,for example, mono- or dihydrates or alkoxides. The invention alsocomprises solvates of salts of the compounds according to the invention.The term “prodrug” is taken to mean compounds according to the inventionwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention. These alsoinclude biodegradable polymer derivatives of the compounds according tothe invention. It is likewise possible for the compounds of theinvention to be in the form of any desired prodrugs such as, forexample, esters, carbonates, carbamates, ureas, amides or phosphates, inwhich cases the actually biologically active form is released onlythrough metabolism. Any compound that can be converted in-vivo toprovide the bioactive agent (i.e. compounds of the invention) is aprodrug within the scope and spirit of the invention. Various forms ofprodrugs are well known in the art. It is further known that chemicalsubstances are converted in the body into metabolites which may whereappropriate likewise elicit the desired biological effect—in somecircumstances even in more pronounced form. Any biologically activecompound that was converted in-vivo by metabolism from any of thecompounds of the invention is a metabolite within the scope and spiritof the invention.

The compounds of the invention may be present in the form of theirdouble bond isomers as pure E or Z isomers, or in the form of mixturesof these double bond isomers. Where possible, the compounds of theinvention may be in the form of the tautomers, such as keto-enoltautomers. All stereoisomers of the compounds of the invention arecontemplated, either in a mixture or in pure or substantially pure form.The compounds of the invention can have asymmetric centers at any of thecarbon atoms. Consequently, they can exist in the form of theirracemates, in the form of the pure enantiomers and/or diastereomers orin the form of mixtures of these enantiomers and/or diastereomers. Themixtures may have any desired mixing ratio of the stereoisomers. Thus,for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor non-chiral phases or by re-crystallization from an optionallyoptically active solvent or with use of an optically active acid or baseor by derivatization with an optically active reagent such as, forexample, an optically active alcohol, and subsequent elimination of theradical.

The invention also relates to the use of mixtures of the compoundsaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

An enantiomerically enriched mixture denotes a compound of Formula (I)or related formula having an enantiomeric excess, as measured by methodswell known by one skilled in the art, of 10% or more, preferably 50% ormore, and more preferably more than 95%. Most preferably anenantiomerically enriched mixture denotes a compound of Formula (I) orrelated Formulae having an enantiomeric excess of more than 98%.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organization for chemical compounds and especially organiccompounds. The compounds of invention have been named according to thestandards used in the program AutoNom 2000 or ACD Lab Version 12.01. Thedetermination of the stereochemistry (S) or (R) is performed usingstandard rules of the nomenclature well known by one skilled in the art.The terms indicated for explanation of the above compounds of theinvention always, unless indicated otherwise in the description or inthe claims, have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents. The term “substituted” means that thecorresponding radical, group or moiety has one or more substituents.Where a radical has a plurality of substituents, and a selection ofvarious substituents is specified, the substituents are selectedindependently of one another and do not need to be identical. Eventhough a radical has a plurality of a specific-designated substituentthe expression of such substituent may differ from each other (e.g.methyl and ethyl). It shall be understood accordingly that a multiplesubstitution by any radical of the invention may involve identical ordifferent radicals. Hence, if individual radicals occur several timeswithin a compound, the radicals adopt the meanings indicated,independently of one another.

The term “alkyl” or “alkyl group” refers to acyclic saturated orunsaturated hydrocarbon radicals, which may be branched orstraight-chain and preferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10carbon atoms, i.e. C₁-C₁₀-alkanyls. Examples of suitable alkyl radicalsare methyl, ethyl, n-propyl, isopropyl, 1,1-, 1,2- or2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-,1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, n-pentyl,iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-, 3- or -methyl-pentyl,n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl,n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n-octadecyl,n-icosanyl, n-docosanyl.

In an embodiment of the invention, alkyl denotes unbranched or branchedalkyl having 1-10 C atoms, in which 1-7H atoms may be replacedindependently from one another by Hal. A preferred embodiment of alkyldenotes unbranched or branched alkyl having 1-6 C atoms, in which 1-4atoms may be replaced independently from one another by Hal. In a morepreferred embodiment of the invention, alkyl denotes unbranched orbranched alkyl having 1-4 C atoms, in which 1-3H atoms can be replacedindependently from one another by Hal, particularly by F and/or Cl. Itis most preferred that alkyl denotes unbranched or branched alkyl having1-6 C atoms. Highly preferred is C₁₋₄-alkyl. A C₁₋₄-alkyl radical is forexample a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl,sec-butyl, tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, especiallymethyl, ethyl, propyl or trifluoromethyl. It shall be understood thatthe respective denotation of alkyl is independently of one another inany radical of the invention.

The terms “cycloalkyl” or “Cyc” for the purposes of this inventionrefers to saturated and partially unsaturated non-aromatic cyclichydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20,preferably 3 to 12, more preferably 3 to 9 carbon atoms. The cycloalkylradical may also be part of a bi- or polycyclic system, where, forexample, the cycloalkyl radical is fused to an aryl, heteroaryl orheterocyclyl radical as defined herein by any possible and desired ringmember(s).

The bonding to the compounds of the general formula (I) can be effectedvia any possible ring member of the cycloalkyl radical. Examples ofsuitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl,cyclopentenyl and cyclooctadienyl.

In an embodiment of the invention, Cyc denotes cycloalkyl having 3-7 Catoms, in which 1-4H atoms may be replaced independently of one anotherby Hal. Preferred is C₃-C₇-cycloalkyl. More preferred isC₄-C₇-cycloalkyl. Most preferred is C₅-C₇-cycloalkyl, i.e. cyclopentyl,cyclohexyl or cycloheptyl, highly preferably cyclohexyl. It shall beunderstood that the respective denotation of Cyc is independently of oneanother in any radical of the invention.

The term “Ar”, “aryl” or “carboaryl” for the purposes of this inventionrefers to a mono- or polycyclic aromatic hydrocarbon systems having 3 to14, preferably 3-12, more preferably 4 to 12, most preferably 5 to 10,highly preferably 6 to 8 carbon atoms, which can be optionallysubstituted. The term “Ar” or “aryl” also includes systems in which thearomatic cycle is part of a bi- or polycyclic saturated, partiallyunsaturated and/or aromatic system, such as where the aromatic cycle isfused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group asdefined herein via any desired and possible ring member of the arylradical. The bonding to the compounds of the general formula (I) can beeffected via any possible ring member of the aryl radical. Examples ofsuited aryl radicals are phenyl, biphenyl, naphthyl, 1-naphthyl,2-naphthyl and anthracenyl, but likewise indanyl, indenyl or1,2,3,4-tetrahydronaphthyl. Preferred carboaryls of the invention areoptionally substituted phenyl, naphthyl and biphenyl, more preferablyoptionally substituted monocylic carboaryl having 6-8 C atoms, mostpreferably optionally substituted phenyl.

Ar and aryl are preferably selected from the following group: phenyl,o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl,o-, m- or p-isopropylphenyl, o-, m- or p-tert.-butylphenyl, o-, m- orp-hydroxyphenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl,o-, m- or p-fluoro-phenyl, o-, m- or p-bromophenyl, o-, m- orp-chlorophenyl, o-, m- or p-sulfonamidophenyl, o-, m- orp-(N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-dimethyl-sulfonamido)-phenyl, o-, m- orp-(N-ethyl-N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-diethyl-sulfonamido)-phenyl, particularly 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.

Irrespective of further substitutions, Het denotes preferably 2- or3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, 4- or5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazoM-, -4- or -5-yl, 1,2,4-triazo-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-iso-5indolyl, indazolyl, 1-, 2-, 4-or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzo-pyrazolyl, 2-, 4-,5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-,5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-,5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7-or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1,4-oxazinyl, furtherpreferably 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl,2,1,3-benzothiadiazol-4-, -5-yl or 2,1,3-benzoxadiazol-5-yl,azabicyclo-[3.2.1]octyl or dibenzofuranyl.

The heterocyclic radicals may also be partially or fully hydrogenated.

Irrespective of further substitutions, Het can thus also denote,preferably, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-,-4- or 5-furyl, tetra-hydro-2- or -3-furyl, 1,3-dioxolan-4-yl,tetrahydro-2- or -3-thienyl, 2,3-di-hydro-1-, -2-, -3-, -4- or-5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-,-2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl,1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,-4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl,1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl,hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl,1,2,3,4-tetrahydro-1-(-2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl,1,2,3,4-tetra-hydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl,2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo-1,4-oxazinyl, furthermorepreferably 2,3-methylene-dioxyphenyl, 3,4-methylenedioxyphenyl,2,3-ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl,3,4-(difluoromethylenedioxy)phenyl, 2,3-dihydro-benzofuran-5- or 6-yl,2,3-(2-oxomethylenedioxy)phenyl or also3,4-di-hydro-2H-1,5-benzodioxepin-6- or -7-yl, furthermore preferably2,3-dihydrobenzofuranyl, 2,3-dihydro-2-oxofuranyl,3,4-dihydro-2-oxo-1H-quinazolinyl, 2,3-dihydrobenzoxazolyl,2-oxo-2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzimidazolyl,1,3-dihydroindole, 2-oxo-1,3-dihydroindole or 2-oxo-2,3-dihydrobenzimidazolyl.

Het preferably denotes piperidinyl, 4-hydroxypiperidinyl, piperazinyl,4-methylpiperazinyl, pyrrolidinyl, morpholinyl, dihydro-pyrazolyl,dihydro-pyridyl, dihydropyranyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, quinolyl, isoquinolyl, benzimidazolyl,benzotriazolyl, indolyl, benzo-1,3-dioxolyl,2,3-dihydro-benzo[1,4]dioxinyl, indazolyl or benzothiadiazolyl, each ofwhich is unsubstituted or mono-, di- or trisubstituted.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro) or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine. Halogenpreferably means a fluorine, chlorine or bromine atom. Fluorine andchlorine are more preferred, particularly when the halogens aresubstituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).It shall be understood that the respective denotation of Hal isindependently of one another in any radical of the invention.

R is preferably straight chain alkyl having 1 to 4 carbon atoms, wherein1 to 5 hydrogen atoms may be replaced by Hal or OH. More preferably R ismethyl or ethyl, and most preferably methyl.

W is preferably N.

A preferably denotes one of the following groups:

A is especially preferred one of the following groups:

Q is preferably

Wherein R^(3′), R⁷ and R⁸ have the meaning given above.

R⁵, R^(5′), R⁶ are preferably independently H, Hal, NR³R⁴, NO₂, phenyl,2-,3- or 4-hydroxy or methoxyphenyl, alkyl, preferably methyl, ethyl,isopropyl, isobutyl, tert-butyl, CF₃, alkoxy (Oalkyl), preferablymethoxy or ethoxy, hydroxyalkylen, preferably CH₂OH, alkoxyalkylenpreferably CH₂OCH₃, COOH, COOalkyl, preferably COOCH₃, COOCH₂CH₃,CONHalkyl, preferably CONHCH₃, CONHCH₂CH₃, CONHisopropyl,CONHcyclohexyl, CONH₂, CON(CH₃)₂, NHCOalkyl, preferably NHCOCH₃,NHCOCH₂CH₃, NHCOPropyl, NHCOisopropyl, NHCOcyclopropyl,NHCO-4-Chloro-phenyl, NHCH₂CH₃, NHCH₂CH₂CH₃, NHCOCH₂CH₂OH,CO—N-morpholinyl, CON(CH₃)CH₂CH₂N(CH₃)₂, CO-1-piperidinyl,CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl,CH₂—N-morpholinyl, CH₂N(H)COCH₃, CH₂N(CH₃)COCH₃, CH₂NH₂, NH₂, CH(OH)CH₃,CH(OR³)CH₃

Most preferably, one of R⁵, R⁶ is H.

R⁷ has preferably the meaning of R⁵ and R⁶. More preferably, R⁷ is H,OCH₃, CH₃, CH₂CH₃, CF₃, Hal, preferably Cl, I, F, NH₂, NO₂, CONHalkyl,preferably CONHCH₃, CON(CH₃)₂, NHCOalkyl such as NHCOCH₃, NHalkyl, suchas NHCH₂CH₂CH₃, COOalkyl, preferably COOCH₂CH₃, hydroxyalkylen,preferably CH₂OH, CH(CH₃)OH, C(CH₃)₂OH, cyclohexyl, cyclopentyl,morpholinyl, tetrahydrofuranyl. Preferably cyclohexyl, cyclopentyl,morpholinyl, tetrahydrofuranyl are substituted by OH. Most preferredare:

R⁸ is preferably H, COalkyl or alkyl. More preferably, R⁸ is H, COmethylor methyl.

Most preferably, m and n simultaneously denote 1.

Accordingly, the subject-matter of the invention relates to compounds offormula (I) as medicament, in which at least one of the aforementionedradicals has any meaning, particularly realize any preferred embodiment,as described above. Radicals, which are not explicitly specified in thecontext of any embodiment of formula (I), sub-formulae thereof or otherradicals thereto, shall be construed to represent any respectivedenotations according to formula (I) as disclosed hereunder for solvingthe problem of the invention. That means that the aforementionedradicals may adopt all designated meanings as each described in theprior or following course of the present specification, irrespective ofthe context to be found, including, but not limited to, any preferredembodiments. It shall be particularly understood that any embodiment ofa certain radical can be combined with any embodiment of one or moreother radicals.

Particularly highly preferred embodiments are those compounds of formula(I) listed in Table 1 and/or physiologically acceptable salts thereof.

TABLE 1 Compounds of formulae (I). OGA enzyme inhibition assay:Configuration OGA No Structure specification IC50 (M)  1

racemic ++++  2

racemic ++++  3

racemic ++++  4

racemic +++  5

racemic ++++  6

racemic +++  7

racemic ++++  8

racemic ++++  9

racemic ++++  10

racemic ++++  11

racemic +++  12

racemic ++++  13

racemic ++++  14

racemic ++  15

racemic ++++  16

racemic ++++  17

Chiral HPLC Method P: 1st eluting compound ++++  18

Chiral HPLC Method P: 2nd eluting compound +  19

racemic +++  20

racemic +++  21

racemic +++  22

racemic ++  23

racemic ++++  24

racemic ++  25

racemic +++  26

racemic ++  27

racemic +  28

racemic ++  29

racemic ++  30

racemic ++  31

racemic +  32

racemic +++  33

racemic ++  34

racemic ++  35

racemic ++++  36

racemic ++  37

racemic ++  38

Chiral HPLC Method P: 1st eluting compound +++  39

racemic +++  40

racemic ++++  41

racemic ++  42

racemic ++  43

racemic ++  44

racemic ++  45

racemic ++++  46

racemic +++  47

racemic ++++  48

racemic ++++  49

racemic ++++  50

racemic ++++  51

racemic +++  52

racemic ++  53

racemic ++  54

racemic ++  55

racemic ++  56

racemic +++  57

racemic +++  58

racemic +++  59

racemic +++  60

racemic ++  61

racemic +++  62

racemic ++++  63

racemic ++++  64

racemic ++++  65

racemic ++++  66

racemic +++  67

racemic +++  68

racemic +++  69

racemic ++  70

racemic ++  71

racemic ++++  72

racemic +++  73

racemic ++++  74

racemic ++++  75

racemic ++++  76

racemic ++++  77

racemic ++++  78

racemic ++++  79

racemic ++++  80

racemic ++++  81

racemic ++++  82

racemic ++++  83

racemic ++++  84

racemic +++  85

racemic +++  86

racemic +++  87

racemic +++  88

racemic +++  89

racemic +++  90

racemic ++++  91

racemic +  92

racemic +++  94

racemic ++  95

racemic ++++  96

racemic ++++  97

racemic ++++  98

racemic ++++  99

racemic ++++ 100

racemic ++++ 101

racemic ++++ 102

racemic ++++ 103

racemic ++++ 104

racemic ++++ 105

racemic +++ 106

racemic +++ 107

racemic ++ 108

Chiral HPLC SFC Method AA: 1st eluting compound + 109

Chiral HPLC SFC Method AA: 2nd eluting compound ++++ 110

racemic ++++ 112

racemic +++ 113

racemic ++++ 114

racemic ++++ 115

racemic ++ 116

racemic ++ 117

racemic +++ 118

racemic ++++ 119

racemic ++++ 120

racemic + 121

racemic ++ 122

racemic ++ 123

racemic ++++ 124

racemic ++++ 125

racemic ++ 126

racemic ++ 135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

231

S-enantiomer 232

S-enantiomer 233

S-enantiomer 234

S-enantiomer 235

S-enantiomer 236

S-enantiomer 237

S-enantiomer 238

S-enantiomer 239

S-enantiomer 240

S-enantiomer 241

S-enantiomer 242

S-enantiomer 243

S-enantiomer 244

S-enantiomer 245

S-enantiomer 246

S-enantiomer 247

S-enantiomer 248

S-enantiomer 249

S-enantiomer 250

S-enantiomer 251

S-enantiomer 252

S-enantiomer 253

S-enantiomer 254

S-enantiomer 255

S-enantiomer 256

S-enantiomer 257

S-enantiomer 258

S-enantiomer 259

S-enantiomer 260

S-enantiomer 261

S-enantiomer 262

S-enantionner 263

S-enantiomer 264

S-enantiomer 265

S-enantiomer 266

S-enantiomer 267

S-enantiomer 268

S-enantiomer 269

S-enantiomer 270

S-enantiomer 271

S-enantiomer 272

S-enantiomer 273

S-enantiomer 274

S-enantiomer 275

S-enantiomer 276

S-enantiomer 277

S-enantiomer 278

S-enantiomer 279

S-enantiomer 280

S-enantiomer 281

S-enantiomer 282

S-enantiomer 283

S-enantiomer 284

S-enantiomer 285

S-enantiomer 286

S-enantiomer 287

S-enantiomer

Activity range of the compounds of Formula (I) is the following:

+ 1 to 10 μM ++ 0.2 to 1 μM +++0.2 to 0.05 μM

++++ below 0.05 μM

Preferred compounds of the present invention demonstrate adequateproperties for use as a drug. In particular such preferred compoundsshow a high solid state stability, high stability in the presence ofliver microsome, high oxidation stability and suitable permeability.Further preferred compounds of the present invention demonstrate theirsuitability as drugs by potent biological activity, such as the level ofO-GlcNAcylation of total proteins measured in brain extracts. Relevanttests for determining such parameters are known by the person skilled inthe art, e.g. solid state stability (Waterman K. C. (2007) Pharm Res24(4); 780-790), stability in the presence of liver microsome (Obach R.S. (1999) Drug Metab Dispos 27(11); 1350-135) and the permeability (e.g.Caco-2 permeability assay, Calcagno A. M. (2006) Mol Pharm 3(1); 87-93);alternatively, they are described in Examples below, such as Example B02describing the determination of O-GlcNAcylation level of total proteinsmeasured in brain extracts. Compounds of the present invention that showa high potency in OGA inhibition assays and one or more of the aboveproperties are especially suitable as a drug for the indicationsmentioned in the present specification.

The compounds according to formula (I) and the starting materials forits preparation, respectively, are produced by methods known per se, asdescribed in the literature, i.e. under reaction conditions that areknown and suitable for said reactions.

Use can also be made of variants that are known per se, but are notmentioned in greater detail herein. If desired, the starting materialscan also be formed in-situ by leaving them in the un-isolated status inthe crude reaction mixture, but immediately converting them further intothe compound according to the invention. On the other hand, it ispossible to carry out the reaction stepwise.

The following abbreviations refer respectively to the definitions below:Ac (acetyl), aq (aqueous), h (hour), g (gram), L (liter), mg(milligram), MHz (Megahertz), μM (micromolar), min (minute), mm(millimeter), mmol (millimole), mM (millimolar), m.p. (melting point),equiv (equivalent), mL (milliliter), μL (microliter), ACN(acetonitrile), AcOH (acetic acid), BINAP(2,2′-bis(disphenylphosphino)-1,1′-binaphthalene, BOC(tert-butoxy-carbonyl), CBZ (carbobenzoxy), CDCl₃ (deuteratedchloroform), CD₃OD (deuterated methanol), CH₃CN (acetonitrile), c-hex(cyclohexane), DCC (dicyclohexyl carbodiimide), DCM (dichloromethane),dppf (1,1′-bis(diphenylphosphino)ferrocene), DIC (diisopropylcarbodiimide), DIEA (diisopropylethylamine), DMF (dimethylformamide),DMSO (dimethylsulfoxide), DMSO-d₆ (deuterated dimethylsulfoxide), EDC(1-(3-dimethyl-amino-propyl)-3-ethylcarbodiimide), ESI (Electro-sprayionization), EtOAc (Ethyl acetate), Et₂O (diethyl ether), EtOH(ethanol), FMOC (fluorenylmethyloxycarbonyl), HATU(dimethylamino-([1,2,3]triazolo[4,5-b]pyridin-3-yloxy)-methylene]-dimethyl-ammoniumhexafluorophosphate), HPLC (High Performance Liquid Chromatography),i-PrOH (2-propanol), K₂CO₃ (potassium carbonate), LC (LiquidChromatography), MD Autoprep (Mass directed Autoprep), MeOH (methanol),MgSO₄ (magnesium sulfate), MS (mass spectrometry), MTBE (Methyltert-butyl ether), Mtr. (4-Methoxy-2, 3, 6-trimethylbenzensulfonyl), MW(microwave), NBS (N-bromo succinimide), NaHCO₃ (sodium bicarbonate),NaBH₄ (sodium borohydride), NMM (N-methyl morpholine), NMR (NuclearMagnetic Resonance), POA (phenoxyacetate), Py (pyridine), PyBOP®(benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate), RT (room temperature), Rt (retention time), SFC(supercritical fluid chromatography), SPE (solid phase extraction), T3P(propylphosphonic anhydride), TBAF (tetra-n-butylammonium fluoride),TBTU (2-(1-H-benzotriazole-1-yl)-1,1,3,3-tetramethyluromium tetrafluoroborate), TEA (triethylamine), TFA (trifluoroacetic acid), THF(tetrahydrofurane), TLC (Thin Layer Chromatography), UV (Ultraviolet).

In general, the compounds according to Formula (I) and related formulaeof this invention may be prepared from readily available startingmaterials. If such starting materials are not commercially available,they may be prepared by standard synthetic techniques. In general, thesynthesis pathways for any individual compound of Formula (I) andrelated formulae will depend on the specific substituents of eachmolecule, such factors being appreciated by those having ordinary skillin the art. The following general methods and procedures describedhereinafter in the examples may be employed to prepare compounds ofFormula (I) and related formulae. Reaction conditions depicted in thefollowing schemes, such as temperatures, solvents, or co-reagents, aregiven as examples only and are not restrictive. It will be appreciatedthat where typical or preferred experimental conditions (i.e. reactiontemperatures, time, moles of reagents, solvents etc.) are given, otherexperimental conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvents used, but such conditions can be determined by a person skilledin the art, using routine optimisation procedures. For all theprotection and deprotection methods, see Philip J. Kocienski, in“Protecting Groups”, Georg Thieme Verlag Stuttgart, New York, 1994 and,Theodora W. Greene and Peter G. M. Wuts in “Protective Groups in OrganicSynthesis”, Wiley Interscience, 3^(rd) Edition 1999.

A “leaving group” LG denotes a chemical moiety which can be removed orreplaced by another chemical group. Throughout the specification, theterm leaving group preferably denotes Cl, Br, I or a reactively modifiedOH group, such as, for example, an activated ester, an imidazolide oralkylsulfonyloxy having 1 to 6 carbon atoms (preferablymethylsulfonyloxy or trifluoromethylsulfonyloxy) or arylsulfonyloxyhaving 6 to 10 carbon atoms (preferably phenyl- or p-tolylsulfonyloxy).When a leaving group LG is attached to an aromatic or heteroaromaticring, LG can denote in addition SO₂-alkyl or F. Radicals of this typefor activation of the carboxyl group in typical acylation reactions aredescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Activated esters areadvantageously formed in situ, for example through addition of HOBt,N-hydroxysuccinimide or HATU.

Depending on the nature of A, R, W, Q, m and n, different syntheticstrategies may be selected for the synthesis of compounds of Formula(I). In the process illustrated in the following schemes, A, R, W, Q, mand n are as above-defined in the description unless otherwisementioned.

Compounds of Formula (I), wherein A, R, W, Q, m and n are defined asabove, can be prepared from alternative compounds of Formula (I), usingsuitable interconversion procedures such as those described hereinafterin the examples, or conventional interconversion procedures well knownby one skilled in the art.

Compound of formula (I) can be separated into compounds of formula (Ia)and (Ib) by chiral chromatography or by chiral resolution,re-crystallization with use of an optically active acid, using methodsknown by one skilled in the art and as described below in the examples(Scheme 1).

Compounds of formula (Ic), wherein A, R, Q, m and n are defined as aboveand W=N, can be prepared by the addition of an amine of formula (II) toa heterocycle of formula (III), where LG is a leaving group as definedabove. This addition can be performed under thermic conditions, heatingboth compounds at a temperature between 50° C. and 200° C., usingregular heating or microwave irradiation, in the presence of a base,such as but not limited to TEA, DIEA, K₂CO₃ or Cs₂CO₃, in a polarsolvent, e.g. DMF, DMA or NMP. Alternatively, this addition can becatalysed by a metal complex, such as but not limited to PdCl₂,Pd(OAc)₂, Pd₂(dba)₃ in the presence of a ligand, e.g. BINAP, o-Tol₃P,X-Phos, and a base, e.g. NaOtBu, Cs₂CO₃ or K₂CO₃, in a suitable solventor solvent mixture, for example dioxane, Toluene/MeOH, at a temperaturebetween RT to 150° C., preferably at RT, for a few hours, e.g. one hourto 24 h (Scheme 2). Amine of formula (II) is obtained after deprotectionof compound (IVa). PG is a suitable protecting group, which iscompatible with the chemistry described below, such as but not limitedto BOC. It can be removed under acidic conditions, such as but notlimited to HCl in MeOH or dioxane or TFA in DCM, yielding isolation ofamine (II).

Compounds of formula (Id), wherein A, R, Q, m and n are defined as aboveand W=CH, can be prepared from an ester (IVb) using method known by aperson killed in the art and as described in the examples below.Different heterocycles Q can be prepared from ester functionality, suchas but not limited to oxadiazole, thiadiazole and thiazole, (Jakopin, Z.et al. Curr. Org. Chem. 2008, 12, 850-898. Hemming, K. Science ofSynthesis, 2004, 13, 127-184. Augustine, J. K. et al. Tetrahedron, 2009,65, 9989-9996. 37. Kempson, J. Name Reactions in Heterocyclic Chemistry11 (2011), 299-308). Depending on the nature of Q, compound of formula(Id) can be obtained from compound (IVc) by displacement of the leavinggroup LG, as defined above, in the presence of a base such as but notlimited to Cs₂CO₃ in a polar solvent, e.g. DMF, DMSO or NMP (Scheme 3).Alternatively compound of formula (Id) can be prepared by metalcatalysed cross coupling reaction with a suitable boronic acid (Va) orester (Vb) and an heterocycle of formula (III), using conditions knownby a person skilled in the art, such as but not limited to Pd(PPh₃)₄ ascatalyst, K₂CO₃ as base, dioxane as solvent at temperature ranging fromRT to 180° C. (Scheme 3). Hydrogenation of the resulting couplingproduct in the presence of a catalyst such as Pd(OH)₂, would yieldcompound of formula (Id) (e.g. Andres, J.-I. et al. J. Med. Chem. 2012,55, 8685-8699) (Scheme 3).

Compound of formula (IV), wherein A, R, W, Q, m and n are defined asabove and Y¹ is a protecting group PG when W=N or an ester when W=CH,can be prepared from the corresponding ketone (IX) by reductiveamination with amine (VI), using conditions known to the one skilled inthe art, such as but not limited to the use of NaBH(OAc)₃ as reducingagent, in the presence of one equivalent of AcOH in DCE. Alternatively,reductive amination can be performed in two steps, with first imineformation, that can be catalysed by Ti(OiPr)₄, followed by reductionwith suitable reducing agent, such as but not limited to NaBH₄ in MeOH(Abdel-Magid, A. F. at al. J. Org. Chem. 1996, 61, 3849-3862).Alternatively, ketone (IX) can be reduced into the corresponding alcohol(VIII) using usual reductive agents such as NaBH₄ in an alcoholicsolvent, such as MeOH. Alcohol functionality can be then transformedinto a suitable leaving group, such as but not limited to Cl or OMs,using conditions known to a person skilled in the art. The addition ofamine (VI) to intermediate (VII) would yield the formation of compound(IV).

Alternatively, compound of formula (X), wherein W, Q, m and n aredefined as above and PG is a suitable protecting group, such as but notlimited to BOC, can be prepared from amine (XI), from compounds (XII),wherein m, n and PG are defined as above and Y² is an ester or a leavinggroup, or from compounds (XIIIa) or (XIIIb) (Scheme 5).

When W is N, compound of formula (X) can be prepared by the addition ofan amine of formula (XI) to a heterocycle of formula (III), where LG isa leaving group as defined above. This addition can be performed underthermic conditions or can be catalysed by a metal complex, usingconditions known by a person skilled in the art and as described belowin the examples.

When W is CH, compound of formula (X) can be prepared from an ester(XII), wherein Y²=COOR and W=CH, using method known by a person skilledin the art and as described in the examples below. Differentheterocycles Q can be prepared from ester functionality, such as but notlimited to oxadiazole, thiadiazole and thiazole, (Jakopin, Z. et al.Curr. Org. Chem. 2008, 12, 850-898. Hemming, K. Science of Synthesis,2004, 13, 127-184. Augustine, J. K. et al. Tetrahedron, 2009, 65,9989-9996. 37. Kempson, J. Name Reactions in Heterocyclic Chemistry II(2011), 299-308). Depending on the nature of Q, compound of formula (X)can be obtained from compound (XII), wherein W is CH and Y²=LG asdefined above, by displacement of the leaving group LG in the presenceof a base such as but not limited to Cs₂CO₃ in a polar solvent, e.g.DMF, DMSO or NMP. Compound of formula (X), wherein Q is a thiazole, canbe obtained from compound (XII), wherein Y² is anaminomethanecarbothioyl group, and a suitable alpha-bromo ketone, usingconditions know by a person skilled in the art.

Alternatively, compound of formula (X) can be prepared by metalcatalysed cross coupling reaction with a suitable boronic acid (XIIIa)or ester (XIIIb), and a heterocycle of formula (III), using conditionsknown by a person skilled in the art, such as but not limited toPd(PPh₃)₄ as catalyst, K₂CO₃ as base, dioxane as solvent at temperatureranging from RT to 180° C. (Scheme 5). Hydrogenation of the resultingcoupling product in the presence of a catalyst such as Pd(OH)₂, wouldyield compound of formula (X) (e.g. Andres, J.-I. et al. J. Med. Chem.2012, 55, 8685-8699) (Scheme 5).

PG is a suitable protecting group, which is compatible with thechemistry described above, such as but not limited to BOC. It can beremoved under acidic conditions, such as but not limited to HCl in MeOHor dioxane or TFA in DCM, yielding isolation of amine (XIV). It can befurther transformed into compound of formula (I) by reductive alkylationwith ketone of formula (IX), following conditions well known by a personskilled in the art, as described in the examples (Abdel-Magid, A. F. atal. J. Org. Chem. 1996, 61, 3849-3862). Alternatively, amine (XIV)addition to compound (VII), prepared as described above and in theexamples, would yield the formation of compound of formula (I).

Amine of formula (II) can be separated into amines of formula (IIa) and(IIb) by chiral chromatography or chiral resolution byre-crystallization with an optically active acid, using methods known byone skilled in the art and as described below in the examples (Scheme6).

Alternatively, amines of formula (IIa) and (IIb) can be synthesized fromchiral amines (XVIa) and (XVIb) respectively. Addition of amines (XVIa)and (XVIb) to reagent (XV), wherein PG is a protecting group, e.g. BOCor SO₂Tol and LG is a leaving group, e.g. Cl, would yield the formationof protected amines (IVe) and (IVf) respectively (Thiel, 0. R. et al. J.Org. Chem. 2008, 73, 3508-3515). Deprotection conditions need to beselected based on the nature of the PG, such as HCl in dioxane or MeOHor TFA in DCM for BOC protecting group. Alternatively a mixture of HBr,AcOH and 4-hydroxybenzoic acid or a mixture of H₂SO₄ and trifluoroaceticacid at temperatures ranging from RT to 100° C. would be used to cleavea sulfonamide protecting group, such as para-toluene sulfonamide

For the preparation of amines of formula (XVIa) and (XVIb), ketone offormula (IX) can be transformed into chiral imine (XVIII), reacting witha chiral auxiliary, such as but not limited to tert-butanesulfinamidegroup in the presence of titanium ethoxide (Ellman J. A. et al. Acc.Chem. Res. 2002, 35, 984-995). It can be further transformed intosulfinamide (XVIIa) or (XVIIb), depending on the conditions used for thereduction step, as described in the reference from Ellman J. A. et al.J. Org. Chem. 2007, 72, 626-629.

Alternatively aldehyde of formula (XIX) can be transformed into alcoholof formula (VIII) with addition of a suitable nucleophile, such as butnot limited to a Grignard reagent (Scheme 9). In another process, ketoneof formula (IXa) can be obtained by Stille cross coupling reactionbetween aryl halide (XX) and tributyl(1-ethoxyvinyl)tin in the presenceof a catalyst, such as but not limited to Pd(PPh₃)₂Cl₂ in toluene attemperatures ranging from RT to 110° C. (Scheme 10).

When a reaction is preferably performed under basic conditions, asuitable base might be selected from metal oxides, e.g. aluminum oxide,alkaline metal hydroxide (potassium hydroxide, sodium hydroxide andlithium hydroxide, inter alia), alkaline earth metal hydroxide (bariumhydroxide and calcium hydroxide, inter alia), alkaline metal alcoholates(potassium ethanolate and sodium propanolate, inter alia), alkalinemetal carbonates (e.g., sodium bicarbonate) and several organic bases(e.g., N,N-diisopropylethylamine, piperidine or diethanolamine, interalia).

The reaction is generally carried out in an inert solvent. Suitableinert solvents are, for example, hydrocarbons, such as hexane, petroleumether, benzene, toluene or xylene; chlorinated hydrocarbons, such astrichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroformor dichloromethane; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether, ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid, aceticacid or trifluoroacetic acid (TFA); nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to TFA, DMF,dichloromethane, THF, H₂O, methanol, tert. butanol, tert. amylalcohol,triethylamine or dioxane.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −80° C.and 140° C., normally between −50° C. and 120° C., preferably between−20° C. and 100° C.

The compounds of formula (I) and sub-formulae thereof are accessible viathe routes above. The starting materials, are usually known to theskilled artisan, or they can be easily prepared by known methods.

The compounds of formula (I) can be modified, like hydrogenated ormetal-reduced, to remove the chlorine, or put into a substitutionreaction, and/or to be transformed with an acid or base into a salt,preferably with a strong acid. Numerous papers and methods are availableand useful for the one skilled in the art in respect for organicchemistry, chemical strategies and tactics, synthetic routes, protectionof intermediates, cleavage and purification procedure, isolation andcharacterization. General chemical modifications are known to the oneskilled in the art. Halogenation of aryls or hydroxy substitution byhalogens of acids, alcohols, phenols, and their tautomeric structurescan be preferably carried out by use of POCl₃, or SOCl₂, PCl₅, SO₂Cl₂.In some instances oxalyl chloride is also useful. Temperatures can varyfrom 0° C. to reflux depending on the task to halogenate a pyridonestructure or a carboxylic acid or a sulfonic acid. Time will also beadjusted from minutes to several hours or even over night. Similarly,alkylation, ether formation, ester formation, amide formation are knownto the one skilled in the art. Arylation with aryl boronic acids can beperformed in presence of a Pd catalyst, appropriate ligand and base,preferably a carbonate, phosphate, borate salt of sodium, potassium orcesium. Organic bases, like Et₃N, DIPEA or the more basic DBU can alsobe used. Solvents can vary too, from toluene, dioxane, THF, diglyme,monoglyme, alcohols, DMF, DMA, NMP, acetonitrile, in some cases evenwater, and others. Commonly used catalysts like Pd (PPh₃)₄, or Pd(OAc)₂,PdCl₂ type precursors of PdO catalysts have advanced to more complexones with more efficient ligands. In C—C arylations, instead of boronicacids and esters, aryl-trifluoroborate potassium salts (Suzuki-Miyauracoupling), organo silanes (Hiyama coupling), Grignard reagents (Kumada),organozinc compounds (Negishi coupling) and stannanes (Stifle coupling)may be useful. This experience can be transferred to N- andO-arylations. Numerous papers and methods are available and useful forthe one skilled in the art in respect of N-arylation and even ofelectron deficient anilines, and with aryl chlorides and anilines aswell as for O-arylation by using Cu catalysis and Pd catalysis.

In the final step of the processes above, a salt of the compounds,preferably those of formula (I), is optionally provided. The saidcompounds according to the invention can be used in their final non-saltform. On the other hand, the present invention also encompasses the useof these compounds in the form of their pharmaceutically acceptablesalts, which can be derived from various organic and inorganic acids andbases by procedures known in the art. Pharmaceutically acceptable saltforms of the compounds according to the invention are for the most partprepared by conventional methods. If the compound according to theinvention contains a carboxyl group, one of its suitable salts can beformed by the reaction of the compound with a suitable base to give thecorresponding base-addition salt. Such bases are, for example, alkalimetal hydroxides, including potassium hydroxide, sodium hydroxide andlithium hydroxide; alkaline earth metal hydroxides, such as magnesiumhydroxide, calcium hydroxide and barium hydroxide; alkali metalalkoxides, for example potassium ethoxide and sodium propoxide; andvarious organic bases, such as piperidine, diethanolamine andN-methyl-glucamine (meglumine), benzathine, choline, diethanolamine,ethylenediamine, benethamine, diethylamine, piperazine, lysine,L-arginine, ammonia, triethanolamine, betaine, ethanolamine, morpholineand tromethamine. The aluminum salts of the compounds according to theinvention are likewise included. In the case of certain compounds of theformula I, which contain a basic center, acid-addition salts can beformed by treating these compounds with pharmaceutically acceptableorganic and inorganic acids, for example hydrogen halides, such ashydrogen chloride, hydrogen bromide or hydrogen iodide, other mineralacids and corresponding salts thereof, such as sulfate, nitrate orphosphate and the like, and alkyl- and monoarylsulfonates, such asmethanesulfonate, ethanesulfonate, toluenesulfonate andbenzenesulfonate, and other organic acids and corresponding saltsthereof, such as carbonate, acetate, trifluoroacetate, tartrate,maleate, succinate, citrate, benzoate, salicylate, ascorbate and thelike. Accordingly, pharmaceutically acceptable acid-addition salts ofthe compounds according to the invention include the following: acetate,adipate, alginate, arginate, aspartate, benzoate, benzenesulfonate(besylate), bisulfate, bisulfite, bromide, butyrate, camphorate,camphorsulfonate, caprate, caprylate, chloride, chlorobenzoate, citrate,cyclamate, cinnamate, cyclopentanepropionate, digluconate,dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethanesulfonate,formate, glycolate, fumarate, galacterate (from mucic acid),galacturonate, glucoheptanoate, gluconate, glutamate, glycerophosphate,hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate,hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,iodide, isethionate, isobutyrate, lactate, lactobionate, malate,maleate, malonate, mandelate, metaphosphate, methanesulfonate,methylbenzoate, monohydrogenphosphate, 2-naphthalenesulfonate,nicotinate, nitrate, oxalate, oleate, palmoate, pectinate, persulfate,phenylacetate, 3-phenylpropionate, phosphate, phosphonate, phthalate,but this does not represent a restriction.

Both types of salts may be formed or interconverted preferably usingion-exchange resin techniques.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

The above-mentioned pharmaceutical salts which are preferred includeacetate, trifluoroacetate, besylate, citrate, fumarate, gluconate,hemisuccinate, hippurate, hydrochloride, hydrobromide, isethionate,mandelate, me-glumine, nitrate, oleate, phosphonate, pivalate, sodiumphosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate,tosylate and tro-meth-amine, but this is not intended to represent arestriction.

The acid-addition salts of basic compounds of the formula (I) areprepared by bringing the free base form into contact with a sufficientamount of the desired acid, causing the formation of the salt in aconventional manner. The free base can be regenerated by bringing thesalt form into contact with a base and isolating the free base in aconventional manner. The free base forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts other-wise correspond tothe respective free base forms thereof.

As mentioned, the pharmaceutically acceptable base-addition salts of thecompounds of the formula I are formed with metals or amines, such asalkali metals and alkaline earth metals or organic amines. Preferredmetals are sodium, potassium, magnesium and calcium. Preferred organicamines are N,N′-dibenzylethylenediamine, chloroprocaine, choline,diethanol-amine, ethylenediamine, N-methyl-D-glucamine and procaine.This is not intended to represent a restriction.

The base-addition salts of acidic compounds of the formula I areprepared by bringing the free acid form into contact with a sufficientamount of the desired base, causing the formation of the salt in aconventional manner. The free acid can be regenerated by bringing thesalt form into contact with an acid and isolating the free acid in aconventional manner. The free acid forms differ in a certain respectfrom the corresponding salt forms thereof with respect to certainphysical properties, such as solubility in polar solvents; for thepurposes of the invention, however, the salts other-wise correspond tothe respective free acid forms thereof.

If a compound of the formula (I) contains more than one group which iscapable of forming pharmaceutically acceptable salts of this type, theformula I also encompasses multiple salts. Typical multiple salt formsinclude, for example, bitartrate, diacetate, difumarate, dimeglumine,di-phosphate, disodium and trihydrochloride, but this is not intended torepresent a restriction.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

Owing to their molecular structure, the compounds of the formula (I) canbe chiral and can accordingly occur in various enantiomeric forms. Theycan therefore exist in racemic or in optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theIntermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the (R)and (S) forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaricacid, di-O-p-toluoyl-tartaric acid, mandelic acid, malic acid, lacticacid, suitable N-protected amino acids (for example N-benzoylproline orN-benzenesulfonylproline), or the various optically activecamphorsulfonic acids. The suitably formed salt with optically activeacid is crystallized using various combinations of solvents, such as butnot limited to methanol, ethanol, isopropanol, THF, water, diethylether, acetone, methyl tert-butyl ethers and other solvents known to theperson skilled in the art. Also advantageous is chromatographicenantiomer resolution with the aid of an optically active resolvingagent (for example dinitrobenzoylphenylglycine, cellulose triacetate orother derivatives of carbohydrates or chirally derivatised methacrylatepolymers immobilised on silica gel). Suitable eluents for this purposeare aqueous or alcoholic solvent mixtures, such as, for example,hexane/isopropanol/acetonitrile, for example in the ratio 82:15:3.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimize pharmacokinetic parameters whileretaining desirable in-vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In-vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the formula (I) with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the formula (I) are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

A further aspect of the invention relates to the use of compoundsaccording to formula (I) and/or physiologically acceptable salts thereoffor inhibiting a glycosidase. Such use may be therapeutic ornon-therapeutic in character. The term “inhibition” denotes anyreduction in glycosidase activity, which is based on the action of thespecific inventive compounds capable to interact with the targetglycosidase in such a manner that makes recognition, binding andblocking possible. It shall be understood that the compounds of theinvention finally interact with the target to unfold the effect. Thecompounds are characterized by such an appreciable affinity to at leastone glycoside hydrolase which ensures a reliable binding and preferablya complete blocking of glycosidase activity. More preferably, thesubstances are mono-specific in order to guarantee an exclusive anddirected recognition with the chosen single glycosidase target. In thecontext of the present invention, the term “recognition”—without beinglimited thereto—relates to any type of interaction between the specificcompounds and the target, particularly covalent or non-covalent bindingor association, such as a covalent bond, hydrophobic/hydrophilicinteractions, van der Waals forces, ion pairs, hydrogen bonds,ligand-receptor interactions, and the like. Such association may alsoencompass the presence of other molecules such as peptides, proteins ornucleotide sequences. The present receptor/ligand-interaction ispreferably characterized by high affinity, high selectivity and minimalor even lacking cross-reactivity to other target molecules to excludeunhealthy and harmful impacts to the treated subject.

In a preferred embodiment of the present invention, the glycosidasecomprises glycoside hydrolases, more preferably family 84 glycosidehydrolases, most preferablyO-glycoprotein-2-acetamido-2deoxy-β-D-glucopyranosidase (OGA), highlypreferably a mammalian O-GlcNAcase. It is particularly preferred thatthe compounds of formula (I) according to the invention selectively bindan O-GlcNAcase, e.g. thereby selectively inhibiting the cleavage of2-acetamido-2-deoxy-3-D-glucopyranoside (O-GlcNAc) while they do notsubstantially inhibit a lysosomal β-hexosaminidase.

The compounds according to the invention preferably exhibit anadvantageous biological activity, which is easily demonstrated in enzymeactivity assays as described herein or known from prior art. In suchin-vitro assays, the compounds preferably exhibit and cause aninhibitory effect. IC₅₀ is the concentration of a compound that produces50% of the maximal inhibition for that compound. The glycosidase targetis especially half inhibited by the compounds described herein if theconcentration of the compounds amounts to less than 100 μM, preferablyless than 10 μM, more preferably less than 1 μM, most preferably lessthan 0.2 μM. Most preferably, compounds of Formula (I) exhibit an IC₅₀less than 0.02 μM.

A further aspect of the present invention relates to a method forinhibiting a glycosidase, wherein a system capable of expressing theglycosidase, particularly expressing said glycosidase, is contacted withat least one compound of formula (I) according to the invention and/orphysiologically acceptable salts thereof, under conditions such thatsaid glycosidase is inhibited. In a preferred embodiment of the method,the glycosidase is contacted with a compound selectively inhibitingO-GlcNAcase and more preferably having an IC₅₀ of less than 0.2 μM. Itis also preferred that the method is performed in-vitro and/or that themethod is not practiced on the human body. A cellular system ispreferred in the scope of the method. The cellular system is defined tobe any subject provided that the subject comprises cells. The cellrefers to any type of primary cells or genetically engineered cells,whether in the isolated status, in culture, as cell line, assembled intissue, organs or intact laboratory mammals, provided that they arecapable of expressing the glycosidase. It shall also be understood thatthe cell expresses the glycosidase as inherent pre-condition to put themethods of inhibition into practice. Although it is particularlypreferred that the cells are capable of expressing or do express theglycosidase, it shall not be excluded that glycosidase-deficient cellscan be used and the glycosidase is artificially added to the cellularsystem. The assay of the invention can be even completely performedin-vitro such that the cell is waived but a glycosidase is contactedwith at least one compound of formula (I) according to the inventionand/or physiologically acceptable salts thereof. Hence, an amount ofisolated glycosidase is provided in crude or purified form for thispurpose.

As discussed herein, the glycosidase-signaling pathways are relevant forvarious diseases, preferably neurodegenerative diseases, diabetes,cancer, cardiovascular diseases and stroke. Accordingly, the compoundsaccording to the invention are useful in the prophylaxis and/ortreatment of diseases that are dependent on the said signaling pathwaysby interaction with one or more of them. The present invention thereforerelates to the therapeutic and non-therapeutic use of compoundsaccording to the invention as inhibitors of the signaling pathwaysdescribed herein, preferably of the OGA-mediated signaling.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to modulate glycosidase activity,usually between about one hour and one week. In-vitro treatment can becarried out using cultivated cells from any sample or cell line.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing OGA-dependent signal transduction pathways in animals and/orcell culture models or in the clinical diseases mentioned in thisapplication.

The use according to the previous paragraphs of the specification may beeither performed in-vitro or in-vivo models. The inhibition can bemonitored by the techniques described in the course of the presentspecification. The in-vitro use is preferably applied to samples ofhumans suffering from neurodegenerative diseases, diabetes, cancer,cardiovascular diseases and stroke. Testing of several specificcompounds and/or derivatives thereof makes the selection of that activeingredient possible that is best suited for the treatment of the humansubject. The in-vivo dose rate of the chosen derivative isadvantageously pre-adjusted to the glycosidase susceptibility and/orseverity of disease of the respective subject with regard to thein-vitro data. Therefore, the therapeutic efficacy is remarkablyenhanced. Moreover, the subsequent teaching of the present specificationconcerning the use of the compounds according to formula (I) and itsderivatives for the production of a medicament for the prophylactic ortherapeutic treatment and/or monitoring is considered as valid andapplicable without restrictions to the use of the compound for theinhibition of glycosidase activity, preferably OGA activity, ifexpedient.

A further aspect of the invention relates to a medicament comprising atleast one compound according to the invention and/or pharmaceuticallyusable derivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. A “medicament” in the meaning of theinvention is any agent in the field of medicine, which comprises one ormore compounds of formula (I) or preparations thereof (e.g. apharmaceutical composition or pharmaceutical formulation) and can beused in prophylaxis, therapy, follow-up or aftercare of patients whosuffer from diseases, which are associated with OGA activity, in such away that a pathogenic modification of their overall condition or of thecondition of particular regions of the organism could establish at leasttemporarily.

Consequently, the invention also relates to a pharmaceutical compositioncomprising as active ingredient an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof together with pharmaceuticallytolerable adjuvants and/or excipients.

In the meaning of the invention, an “adjuvant” denotes every substancethat enables, intensifies or modifies a specific response against theactive ingredient of the invention if administered simultaneously,contemporarily or sequentially. Known adjuvants for injection solutionsare, for example, aluminum compositions, such as aluminum hydroxide oraluminum phosphate, saponins, such as QS21, muramyldipeptide ormuramyltripeptide, proteins, such as gamma-interferon or TNF, M59,squalen or polyols.

Furthermore, the active ingredient may be administered alone or incombination with other treatments. A synergistic effect may be achievedby using more than one compound in the pharmaceutical composition, i.e.the compound of formula (I) is combined with at least another agent asactive ingredient, which is either another compound of formula (I) or acompound of different structural scaffold. The active ingredients can beused either simultaneously or sequentially. The present compounds aresuitable for combination with agents known to those of skill in the art(e.g., WO 2008/025170) and are useful with the compounds of theinvention.

In some embodiments, a compound according to the invention, or for useaccording to the invention, may be provided in combination with anyother active agents or pharmaceutical compositions where such combinedtherapy may be useful to modulate O-GlcNAcase activity, for example totreat neurodegenerative, inflammatory, cardiovascular, orimmunoregulatory diseases or any condition described herein. In someembodiments, a compound according to the invention, or for use accordingto the invention, may be provided in combination with one or more agentsuseful in the prevention or treatment of tauopathies and Alzheimer'sdisease. Examples of such agents may include, without limitation,

-   -   Acetylcholine esterase inhibitors (AChEls) such as Aricept®        (Donepezil), Exelon® (Rivastigmine), Razadyne® (Razadyne ER®,        Reminyl®, Nivalin®, Galantamine), Cognex® (Tacrine), NMDA        antagonists such as memantine (Axura®, Ebixa®), Huperzine A,        Phenserine, Debio-9902 SR (ZT-1 SR), Zanapezil (TAK0147),        ganstigmine, NP7557, α7 nicotinic acetylcholine receptor        agonists, 5-HT6 receptor antagonists, M1 muscarinic        acetylcholine receptor agonists and positive allosteric        modulators, etc    -   Tau aggregation inhibitors such as methylene blue, etc    -   Agents blocking tau aggregation seeding and propagation such as        tau antibodies and tau vaccines, etc    -   Microtubule stabilizers such as AL-108, AL-208, paclitaxel, etc    -   Amyloid-β (A β) peptide lowering agents such as β-secretase        (BACE-1) inhibitors, senile plaque-clearing biologics such as Aβ        antibodies and Aβ vaccines

The invention also relates to a set (kit) consisting of separate packsof an effective amount of a compound according to the invention and/orpharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient. The setcomprises suitable containers, such as boxes, individual bottles, bagsor ampoules. The set may, for example, comprise separate ampoules, eachcontaining an effective amount of a compound according to the inventionand/or pharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilized form.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intra-dermal) methods. Such formulationscan be prepared using processes known in the pharmaceutical art by,e.g., combining the active ingredient with the excipient(s) oradjuvant(s).

The pharmaceutical composition of the invention is produced in a knownway using common solid or liquid carriers, diluents and/or additives andusual adjuvants for pharmaceutical engineering and with an appropriatedosage. The amount of excipient material that is combined with theactive ingredient to produce a single dosage form varies depending uponthe host treated and the particular mode of administration. Suitableexcipients include organic or inorganic substances that are suitable forthe different routes of administration, such as enteral (e.g. oral),parenteral or topical application, and which do not react with compoundsof formula (I) or salts thereof. Examples of suitable excipients arewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, e.g. lactose orstarch, magnesium stearate, talc and petroleum jelly.

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multi-dose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilized) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavors.

In a preferred embodiment of the present invention, the pharmaceuticalcomposition is adapted for oral administration. The preparations can besterilized and/or can comprise auxiliaries, such as carrier proteins(e.g. serum albumin), lubricants, preservatives, stabilizers, fillers,chelating agents, antioxidants, solvents, bonding agents, suspendingagents, wetting agents, emulsifiers, salts (for influencing the osmoticpressure), buffer substances, colorants, flavorings and one or morefurther active substances, for example one or more vitamins. Additivesare well known in the art, and they are used in a variety offormulations.

Accordingly, the invention also relates to a pharmaceutical compositioncomprising as active ingredient an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof together with pharmaceuticallytolerable adjuvants for oral administration, optionally in combinationwith at least another active pharmaceutical ingredient. The priorteaching of the present specification concerning administration routeand combination product, respectively, is valid and applicable withoutrestrictions to the combination of both features if expedient.

The terms “effective amount” or “effective dose” or “dose” areinterchangeably used herein and denote an amount of the pharmaceuticalcompound having a prophylactically or therapeutically relevant effect ona disease or pathological conditions, i.e. which causes in a tissue,system, animal or human a biological or medical response which is soughtor desired, for example, by a researcher or physician. A “prophylacticeffect” reduces the likelihood of developing a disease or even preventsthe onset of a disease. A “therapeutically relevant effect” relieves tosome extent one or more symptoms of a disease or returns to normalityeither partially or completely one or more physiological or biochemicalparameters associated with or causative of the disease or pathologicalconditions. In addition, the expression “therapeutically effectiveamount” denotes an amount which, compared with a corresponding subjectwho has not received this amount, has the following consequence:improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder. Theexpression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The respective dose or dosage range for administering the pharmaceuticalcomposition according to the invention is sufficiently high in order toachieve the desired prophylactic or therapeutic effect of reducingsymptoms of the aforementioned diseases. It will be understood that thespecific dose level, frequency and period of administration to anyparticular human will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general state of health, gender, diet, time and route of administration,rate of excretion, drug combination and the severity of the particulardisease to which the specific therapy is applied. Using well-known meansand methods, the exact dose can be determined by one of skill in the artas a matter of routine experimentation. The prior teaching of thepresent specification is valid and applicable without restrictions tothe pharmaceutical composition comprising the compounds of formula (I)if expedient.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. The concentration of the prophylactically ortherapeutically active ingredient in the formulation may vary from about0.1 to 100 wt %. Preferably, the compound of formula (I) or thepharmaceutically acceptable salts thereof are administered in doses ofapproximately 0.5 to 1000 mg, more preferably between 1 and 700 mg, mostpreferably 5 and 100 mg per dose unit. Generally, such a dose range isappropriate for total daily incorporation. In other terms, the dailydose is preferably between approximately 0.02 and 100 mg/kg of bodyweight. The specific dose for each patient depends, however, on a widevariety of factors as already described in the present specification(e.g. depending on the condition treated, the method of administrationand the age, weight and condition of the patient). Preferred dosage unitformulations are those which comprise a daily dose or part-dose, asindicated above, or a corresponding fraction thereof of an activeingredient. Furthermore, pharmaceutical formulations of this type can beprepared using a process which is generally known in the pharmaceuticalart.

Although a therapeutically effective amount of a compound according tothe invention has to be ultimately determined by the treating doctor orvet by considering a number of factors (e.g. the age and weight of theanimal, the precise condition that requires treatment, severity ofcondition, the nature of the formulation and the method ofadministration), an effective amount of a compound according to theinvention for the treatment of neurodegenerative diseases, for exampletauopathies and Alzheimer's disease, is generally in the range from 0.1to 100 mg/kg of body weight of the recipient (mammal) per day andparticularly typically in the range from 1 to 10 mg/kg of body weightper day. Thus, the actual amount per day for an adult mammal weighing 70kg is usually between 70 and 700 mg, where this amount can beadministered as a single dose per day or usually in a series ofpart-doses (such as, for example, two, three, four, five or six) perday, so that the total daily dose is the same. An effective amount of asalt or solvate or of a physiologically functional derivative thereofcan be determined as the fraction of the effective amount of thecompound according to the invention per se. It can be assumed thatsimilar doses are suitable for the treatment of other conditionsmentioned above.

The pharmaceutical composition of the invention can be employed asmedicament in human and veterinary medicine. According to the invention,the compounds of formula (I) and/or physiologically salts thereof aresuited for the prophylactic or therapeutic treatment and/or monitoringof diseases that are caused, mediated and/or propagated by OGA activity.It is particularly preferred that the diseases are neurodegenerativediseases, diabetes, cancer, cardiovascular diseases and stroke, morepreferably neurodegenerative diseases, most preferably one or moretauopathies, highly preferably Alzheimer's disease and dementia. Itshall be understood that the host of the compound is included in thepresent scope of protection according to the present invention.

Another aspect of the present invention relates to compounds of formula(I) according to the invention and/or physiologically acceptable saltsthereof for use in the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byOGA activity. Another aspect of the invention concerns compounds offormula (I) according to the invention and/or physiologically acceptablesalts thereof for use in the prophylactic or therapeutic treatmentand/or monitoring of neurodegenerative diseases, diabetes, cancer,cardiovascular diseases and stroke. The prior teaching of the presentspecification concerning the compounds of formula (I), including anypreferred embodiment thereof, is valid and applicable withoutrestrictions to the compounds according to formula (I) and their saltsfor use in the prophylactic or therapeutic treatment and/or monitoringof neurodegenerative diseases, diabetes, cancer, cardiovascular diseasesand stroke.

Another aspect of the invention relates to a method for treating adisease that is caused, mediated and/or propagated by OGA activity,wherein an effective amount of at least one compound of formula (I)according to the invention and/or physiologically acceptable saltsthereof is administered to a mammal in need of such treatment. Anotheraspect of the invention relates to a method for treatingneurodegenerative diseases, diabetes, cancer, cardiovascular diseasesand stroke, preferably a tauopathy, wherein an effective amount of atleast one compound of formula (I) according to the invention and/orphysiologically acceptable salts thereof is administered to a mammal inneed of such treatment. The preferred treatment is an oraladministration. The prior teaching of the invention and its embodimentsis valid and applicable without restrictions to the methods of treatmentif expedient.

The neurodegenerative disease or condition is more preferably selectedfrom the group of one or more tauopathies and Alzheimer's disease,Amyotrophic lateral sclerosis (ALS), Amyotrophic lateral sclerosis withcognitive impairment (ALSci), Argyrophilic grain disease, Behaviorvariant frontotemporal dementia (bvFTD), Bluit disease, Bluit disease,Corticobasal degeneration (CBP), Dementia pugilistica, Dementia withLewy Bodies, Diffuse neurofibrillary tangles with calcification, Down'ssyndrome, Familial British dementia, Familial Danish dementia,Frontotemporal dementia with parkinsonism linked to chromosome 17(FTDP-17), Frontotemporal Lobar Degeneration (FTLD), Ganglioglioma,Gangliocytoma, Gerstmann-Straussler-Scheinker disease, Globular glialtauopathy, Guadeloupean parkinsonism, Hallevorden-Spatz disease(neurodegeneration with brain iron accumulation type 1), Leadencephalopathy, Lipofuscinosis, Meningioangiomatosis, Multiple systematrophy, Myotonic dystrophy, Niemann-Pick disease (type C),Pallido-ponto-nigral degeneration, Parkinson's disease, Parkinson'sdisease dementia (PDD), Parkinsonism-dementia complex of Guam, Pick'sdisease (PiD), Postencephalitic parkinsonism (PEP), Primary progressiveaphasia, Prion diseases (including Creutzfeldt-Jakob Disease (GJD),Variant Creutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, Kuru,Progressive supercortical gliosis, Progressive supranuclear palsy (PSP),Pure Autonomic Failure, Richardson's syndrome, Subacute sclerosingpanencephalitis, Tangle-only dementia, Tuberous Sclerosis, Huntington'sdisease. Most preferred are one ore more tauopathies and Alzheimer'sdisease.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by OGA activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byOGA activity. Compounds of formula (I) and/or a physiologicallyacceptable salt thereof can furthermore be employed as intermediate forthe preparation of further medicament active ingredients. The medicamentis preferably prepared in a non-chemical manner, e.g. by combining theactive ingredient with at least one solid, fluid and/or semi-fluidcarrier or excipient, and optionally in conjunction with a single ormore other active substances in an appropriate dosage form.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order tobooster the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The medicament can also be used to reducing thelikelihood of developing a disorder or even prevent the initiation ofdisorders associated with OGA activity in advance or to treat thearising and continuing symptoms. The disorders as concerned by theinvention are preferably neurodegenerative diseases, diabetes, cancer,cardiovascular diseases and stroke.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously passed disease.

In the scope of the present invention, compounds of formula (I) areprovided for the first time. The low molecular weight compounds of theinvention are strong and selective glycosidase inhibitors with improvedpassive permeability. The compounds of formula (I) have been shown to becompetitive with PUGNAc, a known OGA inhibitor that binds in thesubstrate pocket. The endogenous substrate is an O-GlcNAcylated protein.O-GlcNAcylation of nuclear and cytoplasmic proteins is one of the mostcommon post-translational modifications in animals and plants. O-GlcNAccycling modulates a number of cellular processes, and evidence ismounting that dysregulation of O-GlcNAcylation plays a role in theetiology of several diseases, including tauopathies and Alzheimer'sdisease. O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) are the twoenzymes that regulate O-GlcNAc cycling. Emerging data suggest thatinhibitors that block OGA may help maintain healthy O-GlcNAc levels intauopathies and Alzheimer's disease patients and thereby inhibit theformation of neurofibrillary tangles. Hence, the current inventioncomprises the use of compounds of formula (I) in the regulation,modulation and/or inhibition of the glycosidase signal cascade, whichcan be advantageously applied as research tool, for diagnosis and/or intreatment of any disorders that are responsive to OGA signaling andinhibition.

The low molecular weight inhibitors can be applied either themselvesand/or in combination with physical measurements for diagnostics oftreatment effectiveness. Medicaments and pharmaceutical compositionscontaining said compounds and the use of said compounds to treatglycosidase-mediated conditions is a promising, novel approach for abroad spectrum of therapies causing a direct and immediate improvementin the state of health, whether in man and animal. The impact is ofspecial benefit to efficiently combat tauopathies and Alzheimer'sdisease, either alone or in combination with other neurodegenerativetreatments.

Due to the surprisingly appreciable inhibitory activity on OGA, alongwith passive permeability, the compounds of the invention can beadvantageously administered at lower doses compared to other less potentor selective inhibitors of prior art while still achieving equivalent oreven superior desired biological effects. In addition, such a dosereduction advantageously leads to less or even no medicinal adverseeffects.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

All the references cited herein are incorporated by reference in thedisclosure of the invention hereby.

The techniques that are essential according to the invention aredescribed in detail in the specification. Other techniques which are notdescribed in detail correspond to known standard methods that are wellknown to a person skilled in the art, or the techniques are described inmore detail in cited references, patent applications or standardliterature. Although methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, suitable examples are described below. The followingexamples are provided by way of illustration and not by way oflimitation. Within the examples, standard reagents and buffers that arefree from contaminating activities (whenever practical) are used. Theexamples are particularly to be construed such that they are not limitedto the explicitly demonstrated combinations of features, but theexemplified features may be unrestrictedly combined again provided thatthe technical problem of the invention is solved. Similarly, thefeatures of any claim can be combined with the features of one or moreother claims.

EXPERIMENTAL PART

The compounds according to Formula (I) can be prepared from readilyavailable starting materials by several synthetic approaches, using bothsolution-phase and solid-phase chemistry protocols or mixed solution andsolid phase protocols. Examples of synthetic pathways are describedbelow in the examples. All reported yields are non optimized yields.Unless otherwise stated, compounds of Formula (I) and related formulaeobtained as a racemic mixture can be separated to provide anenantiomerically enriched mixture or a pure enantiomer.

The commercially available starting materials used in the followingexperimental description were purchased from Aldrich, Sigma, ACROS,ABCR, Combi-Blocks, Matrix, Apollo scientific, Alfa Aesar, etc. unlessotherwise reported.

The HPLC, MS and NMR data provided in the examples described below areobtained as followed:

¹H NMR analyses were carried out using BRUKER NMR, model AV-II andAV-III 400 MHz FT-NMR. Residual signal of deuterated solvent was used asinternal reference. Chemical shifts (5) are reported in ppm in relativeto the residual solvent signal (5=2.50 for ¹H NMR in DMSO-d₆, and 7.26in CDCl₃). s (singlet), d (doublet), t (triplet), q (quadruplet), br(broad), quint (quintuplet).

The MS data provided in the examples described below were obtained asfollowed: Mass spectrum: LC/MS Agilent (ESI/APCI), Chemstration, 1200Series.

LCMS Methods:

LCMS Method A

Method: A-0.1% TFA in H₂O, B-0.1% TFA in ACN: Flow-2.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm+ve mode

LCMS Method B

Method: A-10 mM NH₄HCO₃ in H₂O, B— ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm), −ve mode

LCMS Method C

Method: A-10 mM NH₄HCO₃ in H₂O, B— ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm), −ve mode

HPLC analyses were obtained using Agilent 1200 Series instruments asfollowed using % with UV detection (maxplot).

HPLC Method A

Method: A-0.1% TFA in H₂O, B-0.1% TFA in ACN: Flow—2.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

HPLC Method B

Method: A-10 mM NH₄HCO₃ in H₂O, B— ACN: Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

The chiral HPLC methods described below may preferably be performed onan Agilent 1260 DAD instrument.

Chiral HPLC (Method A):

Mobile Phase: 0.1% DEA in n-HEXANE: IPA: 60:40; COLUMN: CHIRALPAK AD-H(250×4.6) mm, 5 μm, FLOW: 1.0 mL/min

Chiral HPLC (Method B):

Mobile Phase: n-HEXANE: EtOH: 90:10; COLUMN: CHIRALPAK IC (250×4.6) mm,5 μm; FLOW: 1.0 mL\min;

Chiral HPLC (Method C):

Mobile Phase: 0.1% TFA in n-HEXANE: IPA: 60:40; COLUMN: CHIRALcell OD-H(250×4.6) mm, 5 μm, FLOW: 1.0 mL/min

Chiral HPLC (Method D):

Mobile Phase: 0.1% DEA in Hexane:EtOH: 80:20; COLUMN: Chiralcell OJ-Hcolumn (250×4.6) mm, 5 μm; FLOW: 1.0 mL\min

Chiral HPLC (Method P):

Mobile Phase: 0.1% TFA in n-Hexane:EtOH: 60:40; COLUMN: CHIRALPAK AD-H(250×4.6) mm, 5 μm; FLOW: 1.0 mL\min

Chiral HPLC (Method R):

Mobile Phase: 0.1% DEA in Hexane:IPA: 80:20; COLUMN: Chiralcell OJ-Hcolumn (250×4.6) mm, 5 μm; FLOW: 12.0 mL\min

MD Autoprep HPLC Conditions

The mass directed preparative HPLC purifications were performed with amass directed autopurification Fractionlynx from Waters.

MD Autoprep HPLC Method A

0.1% HCOOH in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7μm

MD Autoprep HPLC Method B

0.1% TFA in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm), 7 μm

MD Autoprep HPLC Method C

10 mM NH₄HCO₃ in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm),7 μm

MD Autoprep HPLC Method D

10 mM NH₄OAc in H₂O, B-MeOH or ACN, Column: Symmetry C8 (300 mm×19 mm),7 μm

Prep-HPLC Conditions

Mobile phase: A-10 mM NH₄HCO₃ in H₂O, B-MeOH or ACN, Column: Sunfire C8(19 mm×250 mm) 5 μm or Sunfire C18 (30 mm×250 mm) 10 μm.

The chiral HPLC SFC analysis may preferably be performed on a THAR SFCAMDS Instrument.

Chiral HPLC SFC Method A

COLUMN: YMC Cellulose SB (250×4.6) mm, 5 μm; CO-SOLVENTS: 0.5% DEA inMethanol; FLOW: 10 mL/min

Chiral HPLC SFC Method B:

COLUMN: Lux C2 (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia inMethanol FLOW: 10 mL/min

Chiral HPLC SFC Method C:

COLUMN: YMC Cellulose C (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammoniain Methanol; FLOW: 10 mL/min

Chiral HPLC SFC Method D:

COLUMN: YMC Amylose SA (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia inIPA; FLOW: 10 mL/min

Chiral HPLC SFC Method E:

COLUMN: YMC Amylose SA (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia inMeOH; FLOW: 3 mL/min

Chiral HPLC SFC Method F:

COLUMN: Lux C3 (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia inMethanol; FLOW: 4 mL/min;

Chiral HPLC SFC Method G:

COLUMN: YMC Cellulose SB (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammoniain MeOH; FLOW: 4 mL/min

Chiral HPLC SFC Method H:

COLUMN: Chiralpak ADH (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia inIPA; FLOW: 4 mL/min

Chiral HPLC SFC Method I:

COLUMN: Lux A1 (250×4.6) mm, 5 μm; CO-SOLVENTS: 20 mM Ammonia in IPA;FLOW: 4 mL/min;

Chiral HPLC SFC Method J:

COLUMN: YMC Cellulose SB (250×4.6) mm 5 μm; CO-SOLVENTS: 0.5% DEA inMethanol

FLOW: 5 mL/min

Chiral HPLC SFC Method K:

COLUMN: YMC Cellulose SB (250×4.6) mm, 5 μm; CO-SOLVENTS: 0.5% DEA inMethanol 40%; FLOW: 4 mL/min;

The SFC purifications were performed with a Prep SFC, THAR-SFC 80 andTHAR-SFC 200.

SFC preparative chiral method PA:

COLUMN: YMC Cellulose SB (250×30) mm, 5 μm; CO-SOLVENTS: 0.5% DEA inMethanol 40%; FLOW: 60 mL/min;

The microwave chemistry was performed on a single mode microwave reactorInitiator™ Sixty from Biotage.

General flash chromatography conditions used for the purification ofintermediates or compounds of Formula I: silica gel 230-400 mesh;gradients used as eluent: 10 to 80% EtOAc in petroleum ether or 1 to 15%MeOH in DCM

Intermediate 1: 6-(1-chloroethyl)quinoxaline

Step 1: 1-(quinoxalin-6-yl)ethan-1-one

6-Bromo quinoxaline (2.0 g, 9.5 mmol) in toluene (20 mL) was degassedfor 30 min. To this solution, 1-ethoxy vinyl tributyltin (3.8 g, 10.5mmol) and bis(triphenylphosphine)palladium dichloride (0.67 g, 0.95mmol) were added at rt and stirred for 16 hours at 90° C. The reactionmixture was cooled to rt and filtered through celite. After evaporationof the solvent, 6 N HCl solution in water (20 mL) was added and themixture was stirred for 1 hour at rt. It was concentrated andneutralized with sat. NaHCO₃. The desired product was extracted with DCM(100 mL), dried over Na₂SO₄ and concentrated. The crude product waspurified by column chromatography to afford the title compound (brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.06-9.04 (m, 2H), 8.70 (d, J=2.4Hz, 1H), 8.28 (t, J=2.8 Hz, 1H), 8.16 (d, J=11.6 Hz, 1H), 2.97 (s, 3H).LCMS: (Method A) 173 (M+H), Rt. 2.25 min, 99.06% (Max).

Step 2: 1-(quinoxalin-6-yl)ethan-1-ol

To a stirred solution of 1-(quinoxalin-6-yl)ethan-1-one (0.8 g, 4.65mmol) in dry MeOH (20 mL), sodium borohydride (0.36 g, 9.3 mmol) wasadded portion wise at 0° C. and the resulting mixture was stirred for 1h. It was then concentrated, diluted with DCM (80 mL), washed with water(20 mL), dried over Na₂SO₄ and concentrated. The crude product was takenfor next step without further purification. Yield: 75% (600 mg, darkbrown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.91-8.89 (m, 2H), 8.03 (t,J=11.6 Hz, 2H), 7.87-7.86 (m, 1H), 5.49 (d, J=5.9 Hz, 1H), 4.97 (t,J=6.2 Hz, 1H), 1.42 (d, J=8.6 Hz, 3H). LCMS: (Method A) 175.0 (M+H), Rt.1.89 min, 95.0% (Max).

Step 3: 6-(1-chloroethyl)quinoxaline

To a stirred solution of 1-(quinoxalin-6-yl)ethan-1-ol (0.6 g, 3.46mmol) in dry DCM (10 mL), thionyl chloride (0.5 mL, 6.93 mmol) was addeddropwise at 0° C. and stirred at rt for 1 hour. The reaction mixture wasevaporated to dryness and was used without further purification. Yield:97% (650 mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (s,2H), 7.93 (s, 1H), 7.70-7.68 (m, 2H), 4.46-4.23 (m, 1H), 1.87 (s, 3H).LCMS: (Method A) 193 (M+H), Rt. 3.41 min, 71.4% (Max).

Intermediate 2: 6-(1-(piperazin-1-yl)ethyl)quinoxaline hydrochloride

Step 1: tert-butyl 4-(1-(quinoxalin-6-yl) ethyl)piperazine-1-carboxylate

To a stirred solution of 1-boc piperazine (3.8 g, 20.83 mmol) in dry DMF(40 mL), TEA (8.7 mL, 62.4 mmol) and Intermediate 6 (4 g, 20.83 mmol)were added at rt and the reaction mixture was stirred overnight at 90°C. The reaction mixture was cooled to rt and concentrated under vacuum.To this crude mixture, water (50 mL) was added and the product wasextracted with DCM (150 mL). Organic layer was dried over anhydrousNa₂SO₄ and concentrated to get the crude product. The crude product waspurified by column chromatography to afford the title compound (brownsolid). LCMS: (Method A) 343.2 (M+H), Rt. 2.59 min, 75.3% (Max).

Step 2: 6-(1-(piperazin-1-yl) ethyl) quinoxaline hydrochloride

To a solution of tert-butyl 4-(1-(quinoxalin-6-yl) ethyl)piperazine-1-carboxylate (3.5 g, 10.23 mmol) in methanol (5 mL), dioxaneHCl (35 mL, 10 V) was added at rt and the reaction mixture was stirredat for 2 h. The reaction mixture was concentrated under reduced pressureand then triturated with diethyl ether (15 mL) to afford the titlecompound. Yield: 87% (2.1 g, brown solid). ¹H NMR (400 MHz, DMSO-d₆):8.94 (d, J=6.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.88 (d,J=8.8 Hz, 1H), 3.85 (d, J=6.8 Hz, 1H), 3.54 (t, J=5.2 Hz, 2H), 3.16 (d,J=3.6 Hz, 2H), 3.06-2.96 (m, 1H), 2.92-3.02 (m, 1H), 2.67 (s, 2H),2.55-2.58 (m, 2H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 243.3 (M+H),Rt. 1.36 min, 95.02% (Max).

Intermediate 3: 5-(1-chloroethyl)benzo[d]thiazole

Step 1: 1-(benzo[d]thiazol-5-yl)ethan-1-one

The title compound was prepared according to the procedure described forIntermediate 6, Step 1, using 5-bromobenzo[d]thiazole (3 g, 14 mmol) asstarting material. The crude product was purified by columnchromatography to give the title compound. Yield: 64.5% (1.6 g, paleyellow solid). LCMS: (Method A) 178.0 (M+H), Rt. 2.61 min, 81.8% (Max).Step 2: 1-(benzo[d]thiazol-5-yl)ethan-1-ol

To a stirred solution of 1-(benzo[d]thiazol-5-yl)ethan-1-one (1.6 g, 9.0mmol) in methanol (20 mL), sodium borohydride (683 mg, 18 mmol) wasadded slowly at 0° C. and stirred 1.5 h. The completion of the reactionwas monitored by TLC and the solvents were evaporated at 45° C. undervacuum. The residue was diluted with EtOAc (50 mL) and washed with water(50 mL), brine solution (50 mL) and dried over Na₂SO₄. The organic layerwas evaporated at 40° C. to give the title compound. Yield: 91.9% (1.49g, pale brown solid).LCMS: (Method A) 180.0 (M+H), Rt. 2.35 min, 92.8%(Max).

Step 3: 5-(1-chloroethyl)benzo[d]thiazole

The title was synthesized from 1-(benzo[d]thiazol-5-yl)ethan-1-ol (1.49g, 8.3 mmol), according the general procedure B. The crude product wasused in the next step without further purification. Yield: quantitative(1.64 g, pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.43 (s, 1H),8.19-8.17 (m, 2H), 7.63-7.61 (m, 1H), 5.57-5.52 (m, 1H), 1.87 (d, J=6.7Hz, 3H). LCMS: (Method A) 198.0 (M+H), Rt. 3.98 min, 62.0% (Max).

Intermediate 4: 6-(1-chloroethyl)-2,3-dihydrobenzofuran

Step 1: 2-(2,5-dibromophenoxy)ethan-1-ol

To a stirred solution of 1,4-dibromo-2-fluorobenzene (100 g, 395.2 mmol)in ethylene glycol (510 mL), NMP (50 mL) was added at rt under N₂atmosphere. Then tBuOK (155.2 g, 1383.0 mmol) was added slowly over 10min at 10° C. The reaction mixture was heated at 100° C. for 12 h. Thecompletion of the reaction was monitored by TLC. The reaction mixturewas cooled to rt and diluted with water (200 mL) and stirred for 15 minat rt. The resulting solid was filtered and washed with ethylene glycol(2×30 mL). Water (2200 mL) was added to the filtrate, the solution wascooled to 15° C. and stirred for 1 h. The resulting precipitate wasfiltered and washed with water (2×100 mL), pet ether (2×100 mL) anddried. It was further dried with the addition of toluene and itsevaporation (3×200 mL). It was then use in the next step without furtherpurification. Yield: 77.5% (90 g, pale brown solid). ¹H NMR (400 MHz,CDCl₃): δ 7.41 (d, J=8.4 Hz, 1H), 7.06 (d, J=2.0 Hz, 1H), 7.02 (dd,J=8.4, 2.4 Hz, 1H), 4.14 (t, J=4.4 Hz, 2H), 4.03-4.00 (m, 2H), 2.36 (t,J=6.4 Hz, 1H).

Step 2: 1, 4-dibromo-2-(2-bromoethoxy)benzene

To a stirred solution of 2-(2,5-dibromophenoxy)ethan-1-ol (45 g, 152mmol) in toluene (315 mL) under inert atmosphere, PBr₃ (18.47 g, 68.0mmol) was added slowly at 0° C. The resulting mixture was heated at 90°C. for 2 h. It was cooled to 0° C. and PBr₃ (8.2 g, 30.0 mmol) and water(0.9 mL) were added slowly and the heating was continued at 90° C. for 8h. Completion of the reaction was monitored by TLC. The reaction mixturewas cooled to 10° C. and quenched with 1N NaOH solution (270 mL). Theorganic phase was separated and was washed with water (150 mL), brine(150 mL), dried over Na₂SO₄ and evaporated at 45° C. under vacuum togive the title compound. Yield: 90.8% (99 g, off white solid). ¹H NMR(400 MHz, CDCl₃): δ 7.43 (d, J=8.8 Hz, 1H), 7.05-7.02 (m, 2H), 4.34 (t,J=6.4 Hz, 2H), 3.70 (t, J=6.4 Hz, 2H).

Step 3: 2, 3-dihydrobenzofuran-6-carbaldehyde

To a stirred solution of 1,4-dibromo-2-(2-bromoethoxy)benzene (99 g,275.9 mmol) in dry THF (990 mL) under inert atmosphere and cooled downto −78° C., n-butyl lithium (189 mL, 303.5 mmol, 1.6 M in hexane) wasadded slowly over 30 min. After 1 h, the same amount of n-butyl lithium(189 mL, 303.5 mmol, 1.6 M in hexane) was added slowly over 30 min at-78° C. The reaction mixture was stirred 1 h at −78° C. DMF (40.3 g,551.8 mmol) was then added slowly and the temperature was maintained 45min at −78° C. Reaction mixture was then warmed to 10° C. and quenchedwith a saturated solution of NH₄Cl (450 mL). The reaction mixture wasextracted with EtOAc (2×200 mL). The combined organic layer was washedwith water (200 mL), brine solution (200 mL), dried over Na₂SO₄ andevaporated at 40° C. under reduced pressure to give the title compound.Yield: crude (40.8 g, Pale brown solid). ¹H NMR (400 MHz, CDCl₃): δ 9.93(s, 1H), 7.41-7.39 (m, 2H), 7.28-7.27 (m, 1H), 4.66 (t, J=8.8 Hz, 2H),3.30 (t, J=8.8 Hz, 2H).

Step 4: 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-ol

To a stirred solution 2,3-dihydrobenzofuran-6-carbaldehyde (30 g, 202mmol) in dry THF (300 mL) under inert atmosphere, methyl magnesiumchloride solution (135 mL, 404 mmol, 3 M in THF) was added slowly over30 min at 0° C. The reaction mixture was stirred for 2 h at the sametemperature. Completion of the reaction was monitored by TLC. Reactionmixture was quenched by using a saturated solution of NH₄Cl (250 mL) andextracted with EtOAc (2×100 mL). The combined organic layer was washedwith water (100 mL), brine (100 mL), dried over Na₂SO₄ and evaporated at40° C. under reduced pressure. The resulting crude product was purifiedby flash chromatography (22% EtOAc in pet ether) to give the titlecompound. Yield: 58.6% (19.5 g, Pale Yellow liquid). ¹H NMR (300 MHz,CDCl₃): δ 7.18 (d, J=7.5 Hz, 1H), 6.87 (dd, J=9.4, 1.2 Hz, 2H),4.89-4.83 (m, 1H), 4.59 (t, J=8.7 Hz, 2H), 3.21 (t, J=8.7 Hz, 2H),1.51-1.50 (m, 3H). LCMS: (Method A) 147.2 (M+H-H₂O), Rt. 2.63 min, 94.7%(Max). HPLC: (Method A) Rt 2.61 min, 96.5% (Max).

Step 5: 6-(1-chloroethyl)-2, 3-dihydrobenzofuran

To a stirred solution of 1-(2,3-dihydrobenzofuran-6-yl)ethan-1-ol (9 g,54.0 mmol) in DCM (180 mL), SOCl₂ (19.4 g, 165 mmol) was added at 0° C.The reaction mixture was stirred at rt for 1 h. Completion of thereaction was monitored by TLC. The reaction mixture was concentratedunder reduced pressure at 40° C. The resulting crude mixture wasdissolved in DCM and evaporated two times (2×100 mL) and dried at 40° C.under reduced pressure to give the title compound. Yield: crude (100%)(9.98 g, dark brown liquid). ¹H NMR (400 MHz, CDCl₃): δ 7.16 (d, J=7.6Hz, 1H), 6.92-6.88 (m, 2H), 5.06 (q, J=6.8 Hz, 1H), 4.59 (t, J=8.8 Hz,2H), 3.21 (t, J=8.8 Hz, 2H), 1.84 (d, J=6.8 Hz, 3H).

Intermediate 5: N-(5-(piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamidehydrochloride

Step 1: tert-Butyl4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of 2-amino 5-bromo-1, 3, 4-thiadiazole (10.0 g,55.5 mmol) in dry DMF (100 mL), K₂CO₃ (15.3 g, 111.1 mmol) and 1-bocpiperazine (12.4 g, 66.65 mmol) were added at 0° C. The reaction mixturewas stirred overnight at 80° C. The reaction mixture was concentratedunder vacuum. To the resulting crude solids, DCM (200 mL) was added. TheDCM layer was washed with water (100 mL), brine (100 mL) and, dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified bysilica gel column chromatography to afford the title compound. Yield:76% (12 g, pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.51 (s, 2H),3.39 (d, J=6.9 Hz, 4H), 3.19 (d, J=7.7 Hz, 4H), 1.39 (s, 9H). LCMS:(Method A) 286.1 (M+H), Rt. 2.71 min, 97.6% (Max).

Step 2:tert-Butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl4-(5-amino-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g, 42.09mmol) in pyridine (120 mL), acetic anhydride (5.1 g, 50.5 mmol) wasadded at 0° C. The reaction mixture was stirred overnight at 50° C. Thereaction mixture was concentrated under vacuum and triturated withdiethyl ether (100 mL). The solid obtained was filtered, washed withdiethyl ether (20 mL), dried and taken for next step without any furtherpurification. Yield: 87% (12 g, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 12.07 (br.s, 1H), 3.45-3.34 (m, 8H), 2.11 (s, 3H), 1.42 (s,9H). LCMS: (Method A) 328.0 (M+H), Rt. 3.11 min, 86.3% (Max).

Step 3: N-(5-(Piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamidehydrochloride

To a stirred solution of tert-butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (12.0 g)in dry dioxane (100 mL), HCl in dioxane (100 mL, 4 N) was added and thereaction mixture was stirred at rt for 3 h. The reaction mixture wasconcentrated under vacuum and the resulting crude product was suspendeddiethyl ether (50 mL). The title compound was obtained after evaporationof the solvent. Yield: 93% (9 g, white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 12.07 (br. s, 1H), 3.67 (s, 4H), 3.21 (s, 4H), 2.13 (s, 3H).LCMS: (Method A) 228.0 (M+H), Rt. 0.71 min, 85.3% (Max).

Intermediate 6:2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-onedihydrochloride

Step 1: tert-butyl 3-bromo-2,4-dioxopiperidine-1-carboxylate

To a stirred solution of tert-butyl 2,4-dioxopiperidine-1-carboxylate (1g, 4.69 mmol) in dry CCl₄ (10 mL), N-bromosuccinimide (0.83 g, 4.69mmol) was added at 10° C. The reaction mixture was stirred at 10-15° C.for 2 h. It was then evaporated under reduced pressure. Water (10 mL)was added and the desired product was extracted with EtOAc (2×30 mL).The combined organic layer was dried over Na₂SO₄ and concentrated. Theresulting crude product was purified by column chromatography, affordingthe title product. Yield: 99% (1.4 g, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 5.50 (s, 1H), 3.74-3.71 (m, 2H), 2.69-2.66 (m, 2H), 1.46 (s,9H). LCMS: (Method A) 193.8 (M-Boc+H), Rt. 2.93 min, 81.51% (Max).

Step 2:tert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a stirred solution of tert-butyl4-carbamothioylpiperazine-1-carboxylate (synthesized according toExample 5, Step 1, 1.31 g, 5.36 mmol) in isopropanol (15 mL), tert-butyl3-bromo-2,4-dioxopiperidine-1-carboxylate obtained in the first step(1.3 g, 4.46 mmol) was added at rt. The reaction mixture was stirredovernight at 90° C. It was cooled down to rt and evaporated underreduced pressure. Water (10 mL) was added and the desired product wasextracted with diethyl ether (2×30 mL), dried over Na₂SO₄ andconcentrated, affording the title product. Yield: 74% (1.42 g, yellowsolid). LCMS: (Method A) 239.0 (M-Boc+H), Rt. 0.70 min, 48.39% (Max).

Step 3: 2-(piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-onedihydrochloride

To a stirred solution oftert-butyl-2-(4-(tert-butoxycarbonyl)piperazin-1-yl)-4-oxo-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylateobtained in previous step (1.3 g, 2.96 mmol) in 1,4-dioxane (10 mL), HClin dioxane (4 M solution, 13 mL, 10 V) was added at 0° C. The reactionmixture was stirred for 2 h at rt. It was evaporated and the resultingsolid was triturated with EtOAc (3×20 mL) to afford titled compoundwhich was used without further purification. Yield: 99% (crude) (2.25 g,white solid). LCMS: (Method A) 239.0 (M+H), Rt. 0.663 min, 82.012%(Max).

Intermediate 7: 7-(1-chloroethyl) imidazo [1,2-a] pyridine

Step 1: 7-bromoimidazo [1, 2-a] pyridine

To a stirred solution of 4-bromopyridin-2-amine (5 g, 28.9 mmol,Molekula Biokem Ltd) in EtOH (50 mL), added sodium bicarbonate (7.28 g,86.7 mmol) and chloroacetaldehyde (5 mL, 115 mmol) and refluxed for 16h. The reaction mixture was evaporated under vacuum and water (25 mL)was added to the crude mixture. The resulting solution was extractedwith EtOAc (2×50 mL). The organic layer was dried over anhydrous Na₂SO₄and concentrated. The resulting crude product was purified by flashchromatography. Yield: 63% (3.6 g, brown solid). LCMS: (Method B) 199.0(M+H), Rt. 3.92 min, 94.50% (Max).

Step 2: 1-(imidazo [1, 2-a] pyridin-7-yl) ethan-1-one

To a stirred solution of 7-bromoimidazo [1, 2-a] pyridine (3.6 g, 18.7mmol) in toluene (35 mL), 1-ethoxy vinyl tributyltin (7.3 mL, 20.1 mmol)and bis(triphenylphosphine)palladium chloride (0.64 g, 0.90 mmol) wereadded under inert atmosphere. The reaction mixture was refluxed at 90°C. for 16 h. It was evaporated under vacuum and 6 N HCl solution (20 mL)was added. The resulting mixture was stirred at rt for 1 h andconcentrated under vacuum. It was neutralized with saturated solution ofNaHCO₃ (20 mL) and was extracted with EtOAc (2×50 mL). The organic layerwas dried over anhydrous Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography. Yield: 73% (2.1 g, yellow solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.62-8.61 (m, 1H), 8.34 (d, J=0.8 Hz, 1H),8.14 (d, J=0.8 Hz, 1H), 7.81 (s, 1H), 7.32-7.31 (m, 1H), 2.65 (s, 3H).LCMS: (Method B) 161.0 (M+H), Rt. 3.140 min, 95.59% (Max).

Step 3: 1-(imidazo [1, 2-a] pyridin-7-yl) ethan-1-ol

To a stirred solution of 1-(imidazo [1, 2-a] pyridin-7-yl) ethan-1-one(2.1 g, 13.1 mmol) in MeOH (20 mL), sodium borohydride (0.65 g, 17.0mmol) was added at 0° C. and the mixture was stirred at rt for 1 h. Itwas evaporated under vacuum and water (10 mL) was added. The product wasextracted with DCM (2×50 mL) and the organic layer was washed with brine(10 mL) and dried over anhydrous Na₂SO₄. Solvent was evaporated,affording the titled product. Yield: 98% (2 g, brown liquid). ¹H NMR(400 MHz, DMSO-d6): δ 8.46-8.44 (m, 1H), 7.85 (s, 1H), 7.49 (d, J=1.5Hz, 1H), 7.41 (d, J=1.0 Hz, 1H), 6.86-6.85 (m, 1H), 5.34 (d, J=5.9 Hz,1H), 4.73-4.71 (m, 1H), 1.33 (d, J=8.6 Hz, 3H). LCMS: (Method B) 163.2(M+H), Rt. 2.83 min, 96.00% (Max).

Step 4: 7-(1-chloroethyl) imidazo [1, 2-a] pyridine

To a stirred solution of 1-(imidazo [1, 2-a] pyridin-7-yl) ethan-1-ol(1.1 g, 6.78 mmol) in DCM (10 mL), thionyl chloride was added at 0° C.and the mixture was stirred at rt for 1 h. Volatiles were evaporatedunder vacuum and the crude product was dissolved in DCM (10 mL). Thisprocess was repeated twice to remove any excess of thionyl chloride.Yield: 93% (1.12 g, brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (d,J=9.4 Hz, 1H), 8.36 (d, J=2.5 Hz, 1H), 8.21 (d, J=2.7 Hz, 1H), 8.03 (s,1H), 7.65-7.63 (m, 1H), 5.63-5.61 (m, 1H), 1.82 (d, J=9.0 Hz, 3H). LCMS:(Method A) 181.0 (M+H), Rt. 1.72 min, 97.41% (Max).

Intermediate 8: 7-(1-(Piperazin-1-yl)ethyl)imidazo[1,2-a]pyridinehydrochloride

Step 1: tert-butyl4-(1-(imidazo [1, 2-a] pyridin-7-yl) ethyl)piperazine-1-carboxylate

To a stirred solution of 1-Boc piperazine (1.1 g, 6.11 mmol) in DMF wasadded TEA (2.3 mL, 16.6 mmol) and Intermediate 7 (1.0 g, 5.55 mmol) andstirred at 80° C. for 16 h. The reaction mixture was evaporated undervacuum and water (5 mL) was added. The product was extracted with EtOAc(2×25 mL) and the organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The resulting crude product was purified by flashchromatography, affording the title compound (off white solid). ¹H NMR(400 MHz, CDCl₃): δ 8.13 (d, J=7.0 Hz, 1H), 7.66 (s, 1H), 7.60-7.58 (m,2H), 7.06 (d, J=6.5 Hz, 1H), 3.53-3.51 (m, 5H), 2.54-2.44 (m, 4H),1.46-1.42 (m, 12H). LCMS: (Method A) 331.2 (M+H), Rt. 1.71 min, 75.51%(Max).

Step 2: 7-(1-(Piperazin-1-yl)ethyl)imidazo[1,2-a]pyridine hydrochloride

To a stirred solution of tert-butyl4-(1-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperazine-1-carboxylate (0.7 g,2.12 mmol) in dry dioxane (100 mL), HCl in dioxane (100 mL, 4 N) wasadded and the reaction mixture was stirred at rt for 3 h. The reactionmixture was concentrated under vacuum and the resulting crude productwas suspended in diethyl ether (50 mL). The title compound was obtainedafter evaporation of the solvent. Yield: 99% (0.47 g, off white solid).LCMS: (Method A) 231.3 (M+H), Rt. 0.49 min, 86.4% (Max).

Intermediate 9: Methyl 6-(piperazin-1-yl) nicotinate hydrochloride

Step 1: Tert-butyl 4-(5-(methoxycarbonyl) pyridin-2-yl)piperazine-1-carboxylate

A stirred solution of 1-Boc piperazine (9.5 g, 51.28 mmol, Symax finechemicals) in dry DMF (80 mL), TEA (12.9 mL, 93.24 mmol) and methyl6-chloronicotinate (8 g, 46.62 mmol, combi block chemicals) were added.The reaction mixture was stirred at 80° C. for 14 h. The resultingreaction mixture was cooled to rt and poured in to water (100 mL). Theformed precipitate was filtered to afford the title product. Yield:96.7% (14.5 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.66 (d,J=2.2 Hz, 1H), 7.97 (dd, J=9.1, 2.4 Hz, 1H), 6.88 (d, J=9.1 Hz, 1H),3.79 (s, 3H), 3.66 (t, J=4.7 Hz, 4H), 3.43 (t, J=5.2 Hz, 4H), 1.43 (s,9H). LCMS: (Method A) 322.3 (M+H), Rt. 2.42 min, 99.42% (Max).

Step 2: Methyl 6-(piperazin-1-yl) nicotinate hydrochloride

A stirred solution of tert-butyl 4-(5-(methoxycarbonyl) pyridin-2-yl)piperazine-1-carboxylate (14.5 g, 45.11 mmol) in 1, 4-dioxane (50 mL),HCl in dioxane (4N in dioxane, 145 mL, 10V) was added at rt and theresulting mixture was stirred for 3 h. The white precipitate formed wasfiltered and washed with diethyl ether (25 mL) and EtOAc (2×20 mL) anddried over Na₂SO₄ to afford the title product. Yield: 94.6% (11 g, palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.29 (br s, 2H), 8.69 (d,J=2.0 Hz, 1H), 8.04 (dd, J=8.8, 2.0 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H),3.90 (t, J=4.8 Hz, 4H), 3.81 (s, 3H), 3.18 (br s, 4H). LCMS: (Method A)222.1 (M-35), Rt. 1.40 min, 98.40% (Max).

Intermediate 10: Ethyl 1-(piperidin-4-yl)-1H-pyrazole-4-carboxylatehydrochloride

Step 1: Tert-butyl 4-((methylsulfonyl)-oxy) piperidine-1-carboxylate

To a stirred solution of 4-hydroxy N-Boc-piperidine (8.0 g, 39.7 mmol)and TEA (14 mL, 99.3 mmol) in DCM (80 mL), methane sulfonyl chloride(3.6 mL, 47.6 mmol) was added dropwise at 0° C. and the mixture wasstirred for 2 h at rt. The completion of the reaction was monitored byTLC. The reaction mixture was quenched with water. The organic layer waswashed with water (50 mL) and brine (50 mL), dried over Na₂SO₄ andconcentrated. The resulting title product was taken for the next stepwithout any further purification. Yield: 85% (9.9 g, pale brown oil). ¹HNMR (400 MHz, DMSO-d₆): δ 4.85-4.81 (m, 1H), 3.64-3.60 (m, 2H), 3.20 (s,3H), 3.18-3.16 (m, 2H), 1.94-1.89 (m, 2H), 1.64-1.50 (m, 2H), 1.40 (s,9H). LCMS: (Method A) 180.0 (M-boc), Rt. 2.63 min, 99.8% (ELSD).

Step 2: Tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a stirred solution of ethyl-1-H pyrazole carboxylate (5.0 g, 3.7mmol) in DMF (50 mL), Cs₂CO₃ (23 g, 71.35 mmol) and tert-butyl4-((methylsulfonyl)-oxy) piperidine-1-carboxylate (9.9 g, 35.6 mmol)were added at 5° C. and reaction mixture was stirred at 90° C.overnight. The completion of the reaction was confirmed by TLC. Thereaction mixture was poured into ice cold water. The resulting solid wasfiltered, washed with water (50 mL) and dried under reduced pressure. Itwas used in the next step without any further purification. Yield:

87% (10 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆: δ 8.39 (s, 1H),7.87 (s, 1H), 4.45-4.39 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 4.05-4.02 (m,2H), 2.01-1.98 (m, 2H), 1.85-1.78 (m, 2H), 1.42 (s, 9H), 1.26 (t, J=7.2Hz, 3H). LCMS: (Method A) 222.0 (M-Boc), Rt. 2.77 min, 92.86% (Max).

Step 3: Ethyl 1-(piperidin-4-yl)-1H-pyrazole-4-carboxylate hydrochloride

A stirred solution of tert-butyl 4-(4-(ethoxycarbonyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (10 g, 30.92 mmol) in 1,4-dioxane (50 mL), HClin dioxane (4 M, 100 mL, 10V) was added and the resulting mixture wasstirred at rt for 2 h. The white precipitate formed was filtered andwashed with diethyl ether (25 mL) and EtOAc (2×20 mL) to afford thetitle product. Yield: 92% (7.4 g, off white solid). ¹H NMR (400 MHz,DMSO-d6): δ 9.12 (br s, 1H), 8.92 (br s, 1H), 8.35 (s, 1H), 7.91 (s,1H), 4.57-4.52 (m, 1H), 4.21 (q, J=7.2 Hz, 2H), 3.04-2.88 (m, 4H),2.19-2.13 (m, 4H), 1.25 (t, J=7.2 Hz, 3H).

LCMS: (Method A) 224.2 (M-35), Rt. 1.88 min, 95.2% (Max).

Intermediate 11: N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)acetamidehydrochloride

Step 1: tert-butyl 4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a stirred solution of 4-nitro-1H-pyrazole (2.0 g, 17.7 mmol, combiblock) in dry MeCN (20 mL), potassium carbonate (7.3 g, 53.4 mmol) andtert-butyl 4-((methylsulfonyl)-oxy) piperidine-1-carboxylate (obtainedas described in Step 1 of Intermediate 10, 4.9 g, 17.6 mmol) were addedat 0° C. The reaction mixture was stirred overnight at 80° C. Thereaction mixture was concentrated under vacuum and DCM (200 mL) wasadded to the resulting crude solid. The solution was washed with water(100 mL), brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated.The resulting crude product was purified by flash chromatography to getthe titled compound. Yield: 58% (3 g, pale brown solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.95 (s, 1H), 8.28 (s, 1H), 4.48-4.43 (m, 1H),4.05-4.02 (m, 2H), 2.89-2.86 (m, 2H), 2.04-2.01 (m, 2H), 1.85-1.75 (m,2H), 1.41 (s, 9H).

Step 2: tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-(4-nitro-1H-pyrazol-1-yl)piperidine-1-carboxylate (2.5 g, 6.7 mmol) indry MeOH (30 mL), was added 10% palladium on charcoal (250 mg) undernitrogen atmosphere. The reaction was stirred at rt for 3 h underhydrogen atmosphere. The reaction progress was monitored by TLC. Aftercompletion of reaction, the reaction mixture was filtered through celiteand washed with MeOH. The filtrate was concentrated to get the titlecompound. Yield: 70% (2 g, brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ7.06 (s, 1H), 6.91 (s, 1H), 4.16-4.08 (m, 1H), 4.01-3.98 (m, 2H), 3.77(br s, 2H), 3.21-2.87 (m, 2H), 1.92-1.89 (m, 2H), 1.72-1.41 (m, 2H),1.40 (s, 9H). LCMS: (Method A) 267.3 (M+H), Rt. 1.98 min, 93.97% (Max).

Step 3: tert-Butyl4-(4-acetamido-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a stirred solution of tert-butyl4-(4-amino-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.6 g, 6.0 mmol) inDCM, N-methyl morpholin (0.72 mL, 6.6 mmol) and acetic anhydride (0.56mL, 6.0 mmol) were added at 0° C. The reaction mixture was stirred at rtfor 2 h. The reaction mixture was concentrated under vacuum andtriturated with diethyl ether (10 mL). The resulting solid was filtered,washed with hexane (20 mL), dried and taken for next step without anyfurther purification. Yield: 91.7% (1.7 g, brown solid). ¹H NMR (400MHz, DMSO-d₆): δ 9.90 (s, 1H), 7.87 (s, 1H), 7.40 (s, 1H), 4.32-4.27 (m,1H), 4.03-4.00 (m, 2H), 3.21-2.87 (m, 2H), 1.96 (s, 3H), 1.95-1.91 (m,2H), 1.75-1.71 (m, 2H), 1.42 (s, 9H). LCMS: (Method A) 309.2 (M+H), Rt.3.01 min, 96.36% (Max).

Step 4: N-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)acetamide hydrochloride

To a stirred solution of tert-butyl4-(4-acetamido-1H-pyrazol-1-yl)piperidine-1-carboxylate (1.7 g) in drydioxane (10 mL), HCl in dioxane (17 mL, 4 N) was added and the reactionmixture was stirred at rt for 3 h. The reaction mixture was concentratedunder vacuum and the resulting crude product was triturated in diethylether (20 mL) and dried under vacuum, affording the title product.Yield: 94.2% (1.2 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ10.10 (s, 1H), 9.32 (br s, 1H), 7.88 (s, 1H), 7.43 (s, 1H), 4.46-4.42(m, 1H), 3.36-3.32 (m, 2H), 3.05-3.01 (m, 2H), 2.15-2.10 (m, 4H), 1.97(s, 3H). LCMS: (Method B) 209.2 (M+H), Rt. 1.33 min, 98.71% (Max).

Intermediate 12: Methyl 2-(piperazin-1-yl)pyrimidine-5-carboxylatehydrochloride

Step 1:5-(4-(1-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine

To a stirred solution of methyl 2-chloropyrimidine-5-carboxylate (5 g,28.97 mmol) in dry DMF (60 mL), TEA (12.09 mL, 86.92 mmol) andtert-butyl piperazine-1-carboxylate (5.93 g, 31.87 mmol) were added at0° C. The reaction mixture was heated at 100° C. overnight. It wasconcentrated to half of the volume and filtered. The resulting solid wasdissolved in DCM (35 mL) and washed with water (20 mL), dried overNa₂SO₄ and concentrated affording the title product. Yield: 70% (7 g,off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.81 (s, 2H), 3.84 (t,J=4.8 Hz, 4H), 8.80 (s, 3H), 3.48-3.38 (m, 4H), 1.42 (s, 9H). LCMS:(Method A) 323.3 (M+H), Rt. 4.31 min, 99.89% (Max).

Step 2: Methyl 2-(piperazin-1-yl)pyrimidine-5-carboxylate hydrochloride

To a stirred solution of5-(4-(1-(imidazo[1,2-a]pyridin-7-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-amine(6.9 g, 21.42 mmol) in dry dioxane (30 mL), HCl in dioxane (50 mL, 4 N)was added and the reaction mixture was stirred at rt for 3 h. Thereaction mixture was concentrated under vacuum and the resulting crudeproduct was suspended diethyl ether (50 mL). The title compound wasobtained after evaporation of the solvent. Yield: 98% (4.7 g, off whitesolid). LCMS: (Method A) 223.3 (M-Boc), Rt. 1.62 min, 99.83% (Max).

Intermediate 13: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazinedihydrochloride

Step 1: tert-butyl4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate

To a stirred solution of N-boc piperazine (5.5 g, 29.5 mmol), TEA (11.9g, 11.8 mmol) in DMF (55 mL), Intermediate 4 (7.5 g, 41.3 mmol) wasadded at rt and the resulting mixture was heated at 70° C. overnight.Completion of the reaction was monitored by TLC. The reaction mixturewas concentrated under reduced pressure and the resulting crude mixturewas dissolved in EtOAc (100 mL). The organic layer was washed with water(50 mL), brine (50 mL), dried over Na₂SO₄ and concentrated. The crudeproduct was purified by flash chromatography (12% EtOAc in pet ether aseluent) to give the title compound. Yield: 52% (58% purity) (5.1 g,brown thick oil). ¹H NMR (400 MHz, CDCl₃): δ 7.19-7.12 (m, 1H),6.88-6.77 (m, 2H), 4.62-4.59 (m, 2H), 3.42-3.39 (m, 4H), 3.36-3.31 (m,1H), 3.23-3.18 (m, 2H), 2.44-2.34 (m, 4H), 1.46 (s, 9H), 1.35 (d, J=6.4Hz, 3H). LCMS: (Method A) 333.3 (M+H), Rt. 3.12 min, 58.09% (Max).

Step 2: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazinedihydrochloride

To a stirred solution of tert-butyl4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine-1-carboxylate (5.1 g,15.3 mmol) in 1,4 dioxane (25 mL), HCl solution in dioxane (4 M, 10 V)was added at 0° C. The resulting mixture was stirred at rt for 2 h.Completion of the reaction was monitored by TLC. The reaction mixturewas evaporated at 40° C. under reduced pressure. The resulting productwas triturated with n-hexanes (2×100 mL) and decanted two times. It wasthen dried at 40° C. under reduced pressure to give the title compound.Yield: 66.2% (3.1 g, Off white solid). ¹H NMR (400 MHz, DMSO-d6): δ 7.15(d, J=7.2 Hz, 1H), 6.76-6.71 (m, 2H), 4.36-4.30 (m, 2H), 3.55-3.53 (m,4H), 3.43-3.41 (m, 1H), 3.15-3.11 (m, 2H), 2.53-2.43 (m, 4H), 1.31-1.29(m, 3H). LCMS: (Method A) 233.2 (M+H), Rt. 1.67 min, 90.31% (Max).

Intermediate 14: 5-bromo-2-(piperazin-1-yl)pyrimidine hydrochloride

Step 1: Tert-butyl-4-(5-bromopyrimidin-2-yl) piperazine-1-carboxylate

To a stirred solution of 1-boc piperazine (10.42 g, 56.86 mmol, Symaxfine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and5-bromo-2-chloropyrimidine (10 g, 51.69 mmol, Oakwood chemicals) wereadded at rt and the reaction mixture was stirred at 80° C. for 14 h. Thereaction mixture was cooled to rt and poured into water (100 mL). Theformed precipitate was filtered and washed with diethyl ether (50 mL) toafford the title product. Yield: 84.5% (15 g, off white solid). ¹H NMR(400 MHz, DMSO-d6): δ 8.49 (s, 2H), 3.69 (t, J=5.2 Hz, 4H), 3.40 (t,J=5.1 Hz, 4H), 1.42 (s, 9H). LCMS: (Method A) 345.23 (M+2), Rt. 4.92min, 99.6% (Max).

Step 2: 5-bromo-2-(piperazin-1-yl)pyrimidine hydrochloride

To a stirred solution of tert-butyl-4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (15.0 g, 43.7 mmol) in 1,4-dioxane (50 mL), HClin dioxane (150 mL, 10V, 4N) was added at 0° C. and stirred at rt for 4h. The resulting white precipitate was filtered and was washed with Et₂O(25 mL), EtOAc (2×20 mL) to afford the title product. Yield: 98.2% (12.0g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.40 (br s, 2H), 8.54(s, 2H), 3.93 (t, J=4.8 Hz, 4H), 3.13 (br s, 4H). LCMS: (Method A) 244.9(M-35), Rt. 1.71 min, 99.8% (Max).

Intermediate 15:2-(Piperazin-1-yl)-5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

Step 1: Benzyl 4-carbamothioylpiperazine-1-carboxylate

To a stirred solution of 1-Z-piperazine (8.5 g, 38.5 mmol) in dry THF(100 mL), 1,1-thiocarbonyldimidazole (12.37 g, 69.4 mmol) was added andthe mixture was stirred at 60° C. for 5 h. It was concentrated undervacuum and NH₃ in EtOH (2 N, 300 mL) was added at 0° C. The resultingmixture was stirred at 55° C. for 8 h in an autoclave. It was dilutedwith water (100 mL) and extracted with DCM (2×100 mL). The DCM layer waswashed with water (100 mL), dried over in anhydrous Na₂SO₄ andconcentrated. The resulting crude product was purified by flashchromatography to afford the title product. Yield: 87% (7 g, whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.51 (s, 2H), 7.38-7.31 (m, 5H),5.1 (s, 2H), 3.78 (m, 4H), 3.43-3.33 (m, 4H). LCMS: (Method A) 280.2(M+H), Rt. 2.33 min, 95.4% (Max).

Step 2: tert-butyl2-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate

To a stirred solution of benzyl 4-carbamothioylpiperazine-1-carboxylate(7.0 g, 20.43 mmol) in dry THF (50 mL), triethylamine (5.2 mL, 37.5mmol) and 3-bromo-4-oxo-piperidine-1-carboxylic acid tert-butyl ester(8.3 g, 30.0 mmol) were added at 0° C. and the mixture was stirred for 8h at 90° C. The reaction mixture was concentrated under vacuum. DCM (200mL) was added and the resulting solution was washed with water (100 mL),brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated. The crudeproduct was purified by flash chromatography to give the title product.Yield: 70% (8 g, White solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.37-7.31(m, 5H), 5.1 (s, 2H), 4.37 (s, 2H), 3.59-3.51 (m, 6H), 3.37-3.30 (m,4H), 1.4 (s, 9H). LCMS: (Method A) 459.2.2 (M+H), Rt. 2.65 min, 97.3%(Max).

Step 3: Benzyl4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate

To a stirred solution of tert-butyl2-(4-((benzyloxy)carbonyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate(3.5 g, 7.6 mmol) in DCM, TFA (20% in DCM, 50 mL) was added at 0° C. andthe mixture was stirred for 4 h at rt. Completion of the reaction wasmonitored by TLC. It was concentrated and DCM (200 mL) was added. Theresulting solution was washed with NaHCO₃ (100 mL), brine (100 mL),dried over anhydrous Na₂SO₄ and concentrated. The resulting crudeproduct was used in the next step without further purification. Yield:96% (2.6 g, brown solid). LCMS: (Method B) 359.2 (M+H), Rt. 2.0, 98.7%(Max). ¹H NMR (400 MHz, DMSO-d₆): δ 7.37-7.31 (m, 5H), 5.1 (s, 2H), 3.7(s, 2H), 3.6-3.59 (m, 4H), 3.35-3.32 (m, 4H), 2.93 (t, J=5.6 Hz, 2H),2.49-2.48 (m, 2H).

Step 4: Benzyl4-(5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate

To a stirred solution of benzyl4-(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate(2.9 g, 8.1 mmol) in dry DCM (50 mL), triethylamine (3 mL, 20.2 mmol)and trityl chloride (2.92 g, 10.0 mmol) were added at 0° C. The reactionmixture was stirred at rt for 2 h. It was quenched with iced water. Thephases were separated and the organic phase was washed with water (100mL), brine (100 mL), dried over anhydrous Na₂SO₄ and concentrated. Theresulting crude product was used in the next step without furtherpurification. Yield: 58% (3 g, White solid). ¹H NMR (400 MHz, DMSO-d₆):δ 7.45-7.05 (m, 20H), 5.1 (s, 2H), 3.55-3.1 (m, 4H), 3.33-3.27 (m, 4H),3.22 (m, 2H), 2.8-2.7 (m, 2H), 2.49-2.48 (m, 2H). LCMS: (Method A) 600.8(M+H), Rt. 8.4.min, 47.70% (Max).

Step 5:2-(Piperazin-1-yl)-5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To a stirred solution of benzyl4-(5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)piperazine-1-carboxylate(3.0 g, 5 mmol) in dry ethanol (50 mL), 6N NaOH (15 mL) was added at 0°C. The reaction mixture was stirred at 85° C. for 8 h. Completion of thereaction was monitored by TLC. The reaction mixture was concentrated andDCM (200 mL) was added. The resulting solution was washed with water(100 mL), brine (100 mL), dried over anhydrous Na₂SO₄. After evaporationof the solvents, the crude product was purified by flash chromatographyaffording the title product. Yield: 78% (1.5 g, off-white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.44 (d, J=7.0 Hz, 6H), 7.32 (t, J=7.4 Hz, 6H),7.20 (t, J=7.0 Hz, 3H), 3.21-3.15 (m, 6H), 2.80-2.72 (m, 4H), 2.68-2.65(m, 2H), 2.50-2.42 (m, 3H). LCMS: (Method A) 467.0 (M+H), Rt. 7.26.min,99.4% (Max).

Intermediate 16: 1-(5-bromopyridin-2-yl)piperazine hydrochloride

Step 1: Tert-butyl 4-(5-bromopyridin-2-yl)piperazine-1-carboxylate

To a stirred solution of 1-Boc piperazine (10.6 g, 57.29 mmol, Symaxfine chemicals) in dry DMF (100 mL), TEA (14.43 mL, 103.39 mmol) and5-bromo-2-chloropyrimidine (10 g, 52.08 mmol, Oakwood chemicals) wereadded and the reaction mixture was stirred at 80° C. for 14 h. It wascooled down to rt and poured on iced water (100 mL). The resultingprecipitate was filtered and washed with hexane (50 mL) to afford thetitle compound. Yield: 58.8% (10 g, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.60 (s, 1H), 8.13 (dd, J=8.6, 2.4 Hz, 1H), 7.54 (dd, J=8.4,0.4 Hz, 1H), 3.22-3.20 (m, 4H), 2.61-2.59 (m, 4H), 1.42 (s, 9H). LCMS:(Method A) 343.9 (M+2H), Rt. 5.58 min, 98.9% (Max).

Step 2: 1-(5-bromopyridin-2-yl)piperazine hydrochloride

To a stirred solution of tert-butyl4-(5-bromopyridin-2-yl)piperazine-1-carboxylate (10 g, 29.21 mmol) in1,4-dioxane (50 mL), 4N HCl solution in dioxane (100 mL, 10V) was addedand the mixture was stirred 4 h at rt. The white precipitate formed wasfiltered and residue was washed with diethyl ether (25 mL) to afford thetitle compound. Yield: 95.2% (9 g, off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 10.05 (br s, 2H), 8.21 (d, J=2.4 Hz, 1H), 7.82 (dd, J=9.2,2.4 Hz, 1H), 6.99 (d, J=9.2 Hz, 1H), 3.80-3.77 (m, 4H), 3.33-3.13 (m,4H). LCMS: (Method A) 243.9 (M+2H), Rt. 1.69 min, 99.3% (Max).

Intermediate 17: Tert-butyl 2-chloro-7, 8-dihydropyrido [4, 3-d]pyrimidine-6(5H)-carboxylate

Step 1: 6-benzyl-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine-2,4(1H, 3H)-dione

A stirred solution of ethyl-1-benzyl-4-oxo-3-piperidine carboxylate,hydrochloride (15 g, 50.4 mmol, combi blocks) and urea (6.36 g, 105mmol) in dry MeOH (110 mL), sodium methoxide (16.4 mL, 75.14 mmol, and25% wt. in methanol) was added drop wise at rt and the mixture wasrefluxed for 40 h. It was cooled to 0° C. and filtered. The residue wasstirred with water (40 mL) for 30 min at rt and again cooled to 0° C.and filtered. The residue was washed with diethyl ether (2×20 mL) anddried, affording the title compound. Yield: 60% (7.2 g, Off whitesolid). ¹H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 2H), 7.33-7.32 (m, 4H),7.26-7.25 (m, 1H), 3.56 (s, 2H), 2.68 (s, 2H), 2.55 (t, J=5.2 Hz, 2H),2.26 (t, J=5.2 Hz, 2H). LCMS: (Method A) 258.2 (M+2), Rt. 1.31 min,99.60% (Max).

Step 2: 6-benzyl-2, 4-dichloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d]pyrimidine

To 6-benzyl-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine-2, 4(1H,3H)-dione (7.2 g, 27.9 mmol), POCl₃ (45 mL, 6V) was added slowly at 0°C. and refluxed for 4 h. The reaction mixture was evaporated undervacuum. EtOAc (200 mL) was added and the solution was poured over cold3M NaOH solution. The resulting organic layer was separated and washedwith brine (30 mL), dried over anhydrous Na₂SO₄ and evaporated,affording the title compound. Yield: 79% (6.5 g, brown solid). ¹H NMR(400 MHz, DMSO-d6): δ 7.33-7.32 (m, 5H), 3.77 (s, 2H), 3.56 (s, 2H),2.94 (t, J=7.2 Hz, 2H), 2.80 (t, J=6.8 Hz, 2H). LCMS: (Method A) 296.3(M+2), Rt. 2.50 min, 97.94% (Max).

Step 3: 6-benzyl-2-chloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d]pyrimidine

To the stirred solution of 6-benzyl-2, 4-dichloro-5, 6, 7,8-tetrahydropyrido [4, 3-d] pyrimidine (6 g, 20.4 mmol) in EtOH (120mL), zinc powder (10.65 g, 163 mmol) and ammonium hydroxide (14.2 mL,102 mmol) were added at rt and the mixture was stirred at 78° C. for 15h. It was cooled to rt and filtered through celite. Resulting filtratewas evaporated under vacuum. The resulting crude mixture was dilutedwith EtOAc (150 mL) and washed with water (15 mL). The organic layer wasdried over anhydrous anhydrous Na₂SO₄ and evaporated under vacuum. Theresulting crude product was purified by flash chromatography. Yield: 52%(2.7 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (s, 1H),7.32-7.31 (m, 5H), 3.71 (s, 2H), 3.57 (s, 2H), 2.89 (t, J=7.6 Hz, 2H),2.79 (t, J=7.2 Hz, 2H). LCMS: (Method A) 260.2 (M+2), Rt. 1.86 min,97.15% (Max).

Step 4: 2-chloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d] pyrimidinehydrochloride

To the stirred solution of 6-benzyl-2-chloro-5, 6, 7, 8-tetrahydropyrido[4, 3-d] pyrimidine (2.7 g, 10.4 mmol) in dry DCM (60 mL), 1-chloroethylchloroformate (1.47 mL, 13.5 mmol) was added at 0° C. The reactionmixture was stirred at 0° C. for 15 min and then refluxed for 2 h. Thereaction mixture was evaporated under vacuum and resulting crude mixturewas refluxed with MeOH (30 mL) for 1 h. Then the reaction mixture wascooled to rt and evaporated under vacuum to give title compound. Yield:70% (crude) (1.5 g, brown thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.45(s, 1H), 3.84 (d, J=5.6 Hz, 2H), 3.01 (t, J=8.0 Hz, 2H), 2.76 (t, J=8.0Hz, 2H). LCMS: (Method B) 170.0 (M+2), Rt. 2.16 min, 81.936% (Max).

Step 5: tert-butyl 2-chloro-7, 8-dihydropyrido [4, 3-d]pyrimidine-6(5H)-carboxylate

To the stirred solution of 2-chloro-5, 6, 7, 8-tetrahydropyrido [4, 3-d]pyrimidine hydrochloride (1.8 g, 8.73 mmol) in dry THF (20 mL), TEA (6.1mL, 43.6 mmol) and Boc anhydride (3.8 mL, 17.4 mmol) were added at 0° C.The reaction mixture was stirred at rt overnight. It was diluted withEtOAc (30 mL) and washed with water (10 mL). The organic layer was driedover anhydrous Na₂SO₄ and evaporated under vacuum. The resulting crudeproduct was purified by flash chromatography to give the title compound.Yield: 60% (0.9 g, off white solid). ¹H NMR (400 MHz, DMSO-d6): δ 8.45(s, 1H), 4.56 (s, 2H), 3.66 (t, J=8.0 Hz, 2H), 2.88 (t, J=8.0 Hz, 2H),1.50 (s, 9H). LCMS: (Method A) 270.2 (M+2), Rt. 3.68 min, 76.45% (Max).

Intermediate 18: 2-methyl-1-(6-(piperazin-1-yl)pyridin-3-yl)propan-1-olhydrochloride

Step 1: tert-butyl4-(5-(1-hydroxy-2-methylpropyl)pyridin-2-yl)piperazine-1-carboxylate

To a solution of tert-butyl4-(5-formylpyridin-2-yl)piperazine-1-carboxylate (1.4 g, 4.81 mmol) indry THF (14 mL), isopropyl magnesium chloride (2M in Et₂O) (2.9 mL, 5.77mmol) was added at −10° C. and the reaction mixture was stirred at 0° C.for 2 h. Upon completion (monitored by TLC), the reaction mixture wasquenched with saturated ammonium chloride solution (10 mL) and thelayers were separated. The organic layer was diluted with ethylacetate(15 mL), washed with brine (15 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The crude product was purified by flashcolumn chromatography to afford the titled compound. Yield: 69% (1.1 g,off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.00 (d, J=2.8 Hz, 1H),7.49-7.45 (m, 1H), 6.79-6.82 (m, 1H), 5.00 (d, J=6.0 Hz, 1H), 4.13 (t,J=8.4 Hz, 1H), 3.43-3.33 (m, 8H), 1.78-1.74 (m, 1H), 1.42 (s, 9H), 0.87(d, J=8.80 Hz, 3H), 0.70 (d, J=8.80 Hz, 3H). LCMS: (Method A) 336.2(M+H), Rt. 2.97 min, 96.7% (Max).

Step 2: 2-methyl-1-(6-(piperazin-1-yl)pyridin-3-yl)propan-1-olhydrochloride

To a 0° C. solution of tert-butyl4-(5-(1-hydroxy-2-methylpropyl)pyridin-2-yl)piperazine-1-carboxylate(1.1 g, 3.28 mmol) in dry 1,4-dioxane (11 mL), 4 M HCl in dioxane (4 mL)was added and the reaction mixture was stirred at rt for 3 h. Uponcompletion (monitored by TLC), the reaction mixture was concentrated andtriturated with diethylether (15 mL). The solid was filtered affordingthe titled compound. Yield: 99% (0.9 g, off white solid). LCMS: (MethodA) 236.2 (M+H), Rt. 1.32 min, 96.6% (Max).

Intermediate 19: 6-bromo-3-methylimidazo[1,5-a]pyridine

Step 1: (5-bromopyridin-2-yl)methanamine

To a solution of 5-bromopicolinonitrile (5 g, 27.32 mmol) in THF,BH₃.THF (1M solution) (163.92 mL, 163.92 mmol) was added at rt and themixture was heated to reflux for 2 h. It was then cooled to 0° C. andMeOH (20 mL) and 1N HCl solution were added. The mixture was furtherrefluxed for 7 h. It was quenched with 10% K₂CO₃ solution (500 mL) andextracted with DCM (6×100 mL). The combined organic layer was dried overNa₂SO₄ and concentrated under vacuum affording the title product. It wastaken for next step without any further purification (Yellow solid).LCMS: (Method A) 187.3 (M+H), Rt. 1.33 min, 77.38% (Max).

Step 2: N-((5-bromopyridin-2-yl)methyl)acetamide

To a stirred solution of (5-bromopyridin-2-yl)methanamine (2 g, 10.69mmol) in DCM, Et₃N (2.23 mL, 16.03 mmol) followed by acetyl chloride(0.91 mL, 12.83 mmol) were added at 0° C. The reaction mixture wasstirred at rt for 3 h. It was then diluted with water (15 mL) andextracted with DCM (2×20 mL). The combined organic layer was dried overNa₂SO₄ and concentrated under vacuum to give crude product which wastaken for next step without further purification. Yield: 54% (1.3 g,Yellow solid).LCMS: (Method A) 229.3 (M+H), Rt. 1.61 min, 69.56% (Max).

Step 3: 6-bromo-3-methylimidazo[1, 5-a]pyridine

To a stirred solution of N-((5-bromopyridin-2-yl)methyl)acetamide (1.3g, 5.67 mmol) in toluene (20 mL) at 0° C., POCl₃ (1.05 mL, 11.34 mmol)was added dropwise over 5 min and the mixture was refluxed at 110° C.for 6 h. It was then quenched with water (15 mL) and concentrated underreduced pressure. A saturated NaHCO₃ solution (15 mL) was added and wasextracted with DCM (2×20 mL). The combined organic layer was dried overNa₂SO₄ and concentrated under vacuum. The crude product was purified byflash chromatography (eluent: 2-3% MeOH in DCM), to give the titleproduct (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (s, 1H), 7.50(t, J=12.8 Hz, 1H), 7.32 (s, 1H), 6.78 (dd, J=12.4, 7.2 Hz, 1H), 2.58(s, 3H). LCMS: (Method A) 213.0 (M+H), Rt. 1.54 min, 99.10% (Max).

Intermediate 20:2-methyl-1-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol dihydrochloride

The title compound was synthesized according to the procedure describedfor Intermediate 18, starting from methyl2-chloropyrimidine-5-carboxylate. Yield: 100% (crude) (200 mg, paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.28 (s, 2H), 8.32 (s, 2H),4.19-4.18 (m, 1H), 3.95-3.92 (m, 4H), 3.14-3.13 (m, 4H), 1.83-1.81 (m,1H), 0.85 (d, J=6.4 Hz, 3H), 0.73 (d, J=6.8 Hz, 3H). LCMS: (Method A)237.3 (M+H-2HCl), Rt. 1.81 min, 58.32% (Max). HPLC: (Method A) Rt 1.79min, 89.12% (Max).

Intermediate 21: 4-(4-(methylsulfonyl)-1H-pyrazol-1-yl)piperidinehydrochloride

The title compound was synthesized according to the procedure describedfor Intermediate 10, starting from 4-(methylsulfonyl)-1H-pyrazole.Yield: 92% (0.9 g, white solid). LCMS: (Method A) 230.0 (M+H), Rt. 1.89min, 90.68% (Max).

Intermediate 22: 1-(2-chloropyrimidin-5-yl)cyclohexan-1-ol

To a stirred solution of 5-bromo-2-chloropyrimidine (1 g, 5.2 mmol) inEt₂O cooled to −100° C. was added n-BuLi (1.6 M) (3.88 mL, 6.2 mmol)over a period of 20 min. The mixture was stirred for 45 min at −100° C.Cyclohexanone (1.014 g, 10.34 mmol) was added dropwise at −100° C. andthe mixture was stirred 1 h at the same temperature. It was quenchedwith a saturated solution of NH₄Cl (10 mL) and extracted with EtOAc(2×20 mL). Combined organic layer was washed with brine (10 mL) anddried over Na₂SO₄. After evaporation of the solvent, the crude productwas purified by flash chromatography (eluent: 30% EtOAc in petroleumether) affording the title compound (yellow thick oil). LCMS: (Method A)213.3 (M+H), Rt. 2.908 min, 98.455% (Max).

Intermediate 23: 4-(2-chloropyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

The title compound was synthesized according to the procedure describedfor Intermediate 22, with the addition of tetrahydro pyran-4-one asketone (yellow solid). LCMS: (Method A) 214.9 (M+2H), Rt. 1.47 min,72.0% (Max).

Intermediate 24: 4-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-4-ol

The title compound was synthesized according to the procedure describedfor Intermediate 22, starting with 5-bromo-2-chloropyridine and theaddition of tetrahydro pyran-4-one as ketone (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.78-8.52 (m, 1H), 7.96-7.92 (m, 1H), 7.49-7.46(m, 1H), 5.35 (s, 1H), 3.78-3.72 (m, 4H), 2.04-1.94 (m, 2H), 1.57-1.53(m, 2H). LCMS: (Method A) 214.0 (M+H), Rt. 2.08 min, 76.24% (Max).

Intermediate 25: 3-(6-chloropyridin-3-yl)tetrahydrofuran-3-ol

The title compound was synthesized according to the procedure describedfor Intermediate 22, starting with 5-bromo-2-chloropyridine and theaddition of tetrahydrofuran-3-one as ketone. Yield: 62% (440 mg,Colourless liquid). LCMS: (Method A) 200.0 (M+H), Rt. 1.91 min, 99.02%(Max).

Intermediate 26: 3-(6-chloropyridin-3-yl)oxetan-3-ol

The title compound was synthesized according to the procedure describedfor Intermediate 22, starting with 5-bromo-2-chloropyridine and theaddition of oxetan-3-one as ketone (colourless liquid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.61 (d, J=2.8 Hz, 1H), 8.03 (q, J=8.4 Hz, 1H), 7.55 (d,J=8.4 Hz, 1H), 6.66 (s, 1H), 4.78 (d, J=7.2 Hz, 2H), 4.69 (d, J=7.2 Hz,2H). LCMS: (Method A) 185.9 (M+H), Rt. 1.61 min, 99.20% (Max).

Intermediate 27: 1-(6-chloropyridin-3-yl)cyclohexan-1-ol

The title compound was synthesized according to the procedure describedfor Intermediate 22, starting with 5-bromo-2-chloropyridine and theaddition of cyclohexanone as ketone (white solid). ¹HNMR (400 MHz,DMSO-d₆): δ 8.51 (s, 1H), 7.91 (dd, J=2.8, 8.2 Hz, 1H), 7.44 (d, J=8.4Hz, 1H), 5.01 (s, 1H), 1.75-1.61 (m, 8H), 1.50 (t, J=4.4 Hz, 2H). LCMS:(Method A) 212.0 (M+H), Rt. 2.44 min, 96.05% (Max).

Intermediate 28: 3-(2-chloropyrimidin-5-yl)tetrahydrofuran-3-ol

The title compound was synthesized according to the procedure describedfor Intermediate 22, with the addition of dihydrofuran-3(2H)-one asketone (yellow thick oil). LCMS: (Method A) 201.2 (M+H), Rt. 1.421 min,96.024% (Max).

Intermediate 29: 2-(1-chloroethyl)-1,8-naphthyridine

Step 1: 2-methyl-1,8-naphthyridine

To a stirred solution of 2-amino-3-formyl pyridine (7 g, 57 mmol) inacetone (70 mL), a saturated solution of KOH in methanol (0.5 mL) wasadded and the mixture was stirred at 55° C. for 6 h. Completion of thereaction was monitored by TLC. The mixture was concentrated and theresulting crude product was purified by flash chromatography (Elutant:65-85% EtOAc in pet ether) to give the title compound. Yield: 88.3% (7.3g, pale brown solid). ¹H NMR (400 MHz, CDCl₃): δ 9.10-9.09 (m, 1H),8.18-8.15 (m, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.47-7.39 (m, 1H), 7.29-7.28(m, 1H), 2.84 (s, 3H). LCMS: (Method B) 145.0 (M+H), Rt. 3.06 min,97.85% (Max). HPLC: (Method B) Rt 2.98 min, 98.09% (Max).

Step 2: 1, 8-naphthyridine-2-carbaldehyde

A solution of selenium dioxide (8.61 g, 77.56 mmol) in 1,4 dioxane (140mL) with 0.5 mL of water was stirred at 100° C. for 5 min. The mixturewas cooled down to 0° C. and 2-Methyl-1,8-naphthyridine (7 g, 48.5 mmol)was added dropwise. The mixture was heated again at 100° C. for 5 h.Completion of the reaction was monitored by TLC. The reaction mixturewas filtered through celite bed, washed with EtOAc (50 mL) andconcentrated. The resulting crude mixture was dissolved in EtOAc (150mL) and washed with water (3×60 mL), brine (30 mL), dried over Na₂SO₄and concentrated to give the title compound (brown solid). ¹H NMR (300MHz, DMSO-d₆): δ 10.18 (s, 1H), 9.28-9.27 (m, 1H), 8.74 (d, J=8.1 Hz,1H), 8.63 (d, J=8.1 Hz, 1H), 8.11 (dd, J=8.4, 1.2 Hz, 1H), 7.83-7.79 (m,1H). LCMS: (Method B) 159.0 (M+H), Rt. 2.44 min, 91.59% (Max). HPLC:(Method B) Rt 2.41 min, 87.86% (Max).

Step 3: 1-(1,8-naphthyridin-2-yl)ethan-1-ol

To a stirred solution of 1,8-naphthyridine-2-carbaldehyde (3.3 g, 20.8mmol) in dry THF (100 mL), methyl magnesium chloride in THF (14 mL, 41.7mmol, 3M) was added at 0° C. and stirred 2 h at rt. Completion of thereaction was monitored by TLC. The reaction mixture was quenched withsaturated NH₄Cl solution (20 mL) and extracted with EtOAc. The EtOAclayer was washed with water (2×25 mL), brine (25 mL), dried over Na₂SO₄and concentrated. The resulting crude product was purified by flashchromatography (Elutant: 65-80% EtOAc in pet ether) to give the titlecompound. Yield: 60.6% (2.2 g, brown thick oil). ¹H NMR (300 MHz,CDCl₃): δ 9.16-9.13 (m, 1H), 8.27-8.23 (m, 2H), 7.57-7.53 (m, 2H),5.17-5.10 (m, 1H), 1.68-1.48 (m, 3H). LCMS: (Method B) 175.0 (M+H), Rt.2.86 min, 51.51% (Max). HPLC: (Method A) Rt 0.73 min, 63.62% (Max).

Step 4: 2-(1-chloroethyl)-1,8-naphthyridine

To a stirred solution of 1-(1,8-naphthyridin-2-yl)ethan-1-ol (500 mg,2.87 mmol) in DCM (10 mL), thionyl chloride was added at 0° C. andstirred 1.5 h at rt. Completion of the reaction was monitored by TLC.The reaction mixture was concentrated under vacuum. DCM (20 mL) wasadded and evaporated. This process was repeated twice, affording thetitle product. Yield: 100% (550 mg, brown thick oil). ¹H NMR (300 MHz,DMSO-d₆): δ 9.29-9.27 (m, 1H), 8.89 (dd, J=8.1, 1.8 Hz, 1H), 8.76 (d,J=8.4 Hz, 1H), 8.04 (d, J=8.4 Hz, 1H), 7.96-7.92 (m, 1H), 5.63-5.61 (m,1H), 1.96 (d, J=6.6 Hz, 3H). LCMS: (Method A) 193.0 (M+H), Rt. 1.99 min,75.76% (Max).

Intermediate 30: 1-(6-chloropyridin-3-yl)cyclopentan-1-ol

The title compound was synthesized according to the procedure describedfor Intermediate 22, starting with 5-bromo-2-chloropyridine and theaddition of cyclopentanone as ketone (white solid). ¹H NMR (400 MHz,CDCl₃): δ 8.52 (s, 1H), 7.80 (dd, J=2.4, 8.2 Hz, 1H), 7.31 (dd, J=0.4,8.0 Hz, 1H), 2.04-1.99 (m, 6H), 1.92-1.89 (m, 2H). LCMS: (Method A)198.2 (M+H), Rt. 2.29 min, 89.7% (Max).

Intermediate 31: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-ylmethanesulfonate

Step 1: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-ol

To a stirred solution of 4-Hydroxy piperidine (2.5 g, 24.7 mmol) in dryacetonitrile (10 mL), were added TEA (10.3 mL, 74.1 mmol) and6-(1-chloroethyl)-2,3-dihydrobenzofuran, (4.5 g, 24.7 mmol) at rt andthe mixture was stirred overnight. The reaction mixture was concentratedunder vacuum. To the resulting crude mixture, DCM (50 mL) was added andwas washed with water (20 mL), brine (20 mL), dried over anhydrousNa₂SO₄ and concentrated. The crude product was purified by silica gelcolumn chromatography to afford the titled compound (off white solid).¹H NMR (400 MHz, CDCl₃): δ 7.15 (s, 1H), 6.74-6.73 (m, 2H), 4.54-4.48(m, 4H), 3.14 (t, J=11.6 Hz, 2H), 1.96 (d, J=9.6 Hz, 2H), 1.80-1.61 (m,3H), 1.41-1.20 (m, 6H). LCMS: (Method A) 248.1 (M+H), Rt. 1.67 min,97.8% (Max).

Step 2: 1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-ylmethanesulfonate

To a stirred solution of step1:1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperidin-4-ol (0.2 g, 0.8mmol) in dry DCM (4 mL) were added TEA (0.33 mL, 2.4 mmol) and methanesulphonyl chloride (0.12 mL, 1.6 mmol, Spectro chem) at 0° C. Thereaction mixture was stirred at rt for 4 h. The reaction progress wasmonitored by TLC. After the completion of reaction, the reaction mixturewas diluted with DCM (30 mL) and washed with 10% NaHCO₃ (30 mL)solution. The organic layer was washed with water (30 mL), brine (30 mL)and dried over Na₂SO₄. After evaporation of the solvent, the titlecompound was obtained and was used without further purification. Yield:80.2% (0.2 g, brown thick oil). LCMS: (Method A) 326.3 (M+H), Rt. 2.72min, 55.05% (Max).

Intermediate 33: N-(2-(2-chloropyrimidin-5-yl)propan-2-yl)acetamide

Step 1: 2-(2-chloropyrimidin-5-yl) propan-2-ol

To the reaction mixture of methyl 2-chloropyrimidine-5-carboxylate (2.5g, 14.487 mmol) in THF (10 mL), methyl magnesium chloride (14.487 mL,43.463 mmol) was added drop wise at 0° C. and the mixture was stirred atrt for 30 min. After completion of reaction the reaction mixture waspoured into 50 mL of 1N HCl and extracted with ether. The ether layerwas washed with water, dried over anhydrous Na₂SO₄ and concentrated. Theresulting crude product was purified by flash chromatography (Elutant:55-60% EtOAc in pet ether) to afford title compound (pale yellow solid).¹H NMR (400 MHz, DMSO-d₆): δ 1.48 (s, 6H), 5.51 (s, 1H), 8.84 (s, 2H).LCMS: (Method A) 173.0 (M+H), Rt. 1.659 min, 98.64% (Max).

Step 2: N-(2-(2-chloropyrimidin-5-yl)propan-2-yl)acetamide

To a solution of 2-(2-chloropyrimidin-5-yl) propan-2-ol (1.1 g, 6.376mmol) in MeCN, conc. H₂SO₄ (2.37 mL, 44.637 mmol) was added dropwise at0° C. and the mixture was stirred at rt for 24 h. After completion ofreaction, the reaction mixture was cooled to 0° C. and diluted withNH₄OH solution slowly. Then the reaction mixture was extracted withether. The ether layer was washed with water, dried over Na₂SO₄ andconcentrated. The resulting crude product was purified by flashchromatography to afford title compound (off white). LCMS: (Method A)214.2 (M+H), Rt. 1.662 min, 98.72% (Max).

Intermediate 34: 3-(2-chloropyrimidin-5-yl)oxetan-3-ol

The title compound was synthesized according to the procedure describedfor Intermediate 22, using oxetan-3-one as ketone (off white crystals).¹H NMR (300 MHz, DMSO-d₆): δ 8.95 (s, 2H), 6.85 (s, 1H), 4.78 (s, 4H).LCMS: (Method A) 187.0 (M+H), Rt. 1.321 min, 84.213% (Max).

Intermediate 35: 6-(piperazin-1-yl)isoindolin-1-one, hydrochloride

Step 1: tert-butyl 4-(3-oxoisoindolin-5-yl)piperazine-1-carboxylate

To a degassed solution of 6-bromoisoindolin-1-one (0.7 g, 3.3 mmol),1-Boc piperazine (0.921 g, 4.9 mmol) and sodium tert butoxide (0.95 g,2.5 mmol) in toluene (10 mL), Pd₂(dba)₃ (0.151 g, 0.165 mmol) and BINAP(0.205 g, 0.33 mmol) were added at rt and heated to 80° C. overnight insealed tube. Then the reaction mixture was filtered through celite andconcentrated. Water (4 mL) was added and was extracted with EtOAc (2×10mL). The combined organic layer was dried over Na₂SO₄ and concentratedunder vacuum. The resulting crude product was purified by flashchromatography (Eluent: 5-6% MeOH in DCM). After evaporation, theresulting solid was triturated in Et₂O and filtered, affording the titleproduct (white solid). ¹H NMR (400 MHz, CDCl₃): δ 8.72-8.70 (m, 1H),7.79 (d, J=1.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.26-7.23 (m, 1H), 4.26(s, 2H), 3.49-3.46 (m, 4H), 3.18-3.13 (m, 4H), 1.43 (s, 9H). LCMS:(Method A) 318.0 (M+H), Rt. 2.26 min, 39.9% (Max).

Step 2: 6-(piperazin-1-yl)isoindolin-1-one, hydrochloride

To a stirred solution of tert-butyl4-(5-acetamido-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (0.35 g0.9 mmol) in dry dioxane (4 mL), HCl in dioxane (5 mL, 4 N) was added atrt and the reaction mixture was stirred at rt for 2 h. The reactionmixture was concentrated under vacuum and the resulting crude productwas triturated with Et₂O (20 mL) to get the title compound. Yield: 50%(120 mg, Yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.95 (s, 2H),7.47-7.44 (m, 1H), 7.06-7.02 (m, 1H), 6.76 (s, 1H), 4.35-4.28 (m, 2H),3.41-3.39 (m, 4H), 3.30-3.20 (m, 4H). LCMS: (Method A) 218.2 (M+H), Rt.1.05 min, 65.4% (Max).

Intermediate 36: 5-(piperazin-1-yl)-1, 3,4-thiadiazol-2(3H)-onehydrochloride

Step 1: tert-butyl 4-(hydrazinocarbonothioyl)piperazine-1-carboxylate

To the stirred solution of tert-butyl piperazine-1-carboxylate (5.0 g,26.845 mmol) in THF (50 mL), triethylamine (22.6 mL, 161.072 mmol) andthiocarbonyldiimidazole (9.568 g, 53.690 mmol) were added and stirredfor 2 h at rt. Hydrazine hydrate (2.68 mL, 53.690 mmol) was added andthe reaction mixture was further stirred for 2 h at room temperature.The reaction the reaction mixture was poured into 50 mL of brinesolution and extracted with EtOAc. The EtOAc layer was dried over Na₂SO₄and concentrated under reduced pressure to get crude compound. Theresulting crude product was purified by flash chromatography (Elutant:1-2% MeOH in DCM) to afford title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.10 (s, 1H), 4.43 (s, 2H), 3.84-0.00 (m, 4H),3.57-3.50 (m, 4H), 1.49 (s, 9H). LCMS: (Method A) 262.0 (M+H), Rt. 1.659min, 92.71% (Max).

Step 2: tert-butyl4-(5-oxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate

To the tert-butyl 4-(hydrazinocarbonothioyl)piperazine-1-carboxylate(2.0 g, 7.692 mmol) in DCM (20 mL), triethylamine (3.2 mL, 23.076 mmol)and carbonyldiimidazole (3.74 g, 23.076 mmol) were added at rt andstirred for 4 h at rt. After completion of reaction, the reactionmixture was poured into 50 mL of brine solution and extracted withEtOAc. The EtOAc layer was dried over Na₂SO₄ and concentrated. Theresulting crude product was purified by flash chromatography (Elutant:1-2% MeOH in DCM) to afford title compound. Yield: 52.2% (1.1 g, offwhite). ¹H NMR: (400 MHz, DMSO-d₆): δ 3.54-3.50 (m, 4H), 3.28-3.25 (m,4H), 1.49 (s, 9H). LCMS: (Method A) 287.0 (M+H), Rt. 2.406 min, 99.95%(Max).

Step 3: 5-(piperazin-1-yl)-1, 3,4-thiadiazol-2(3H)-one hydrochloride

The stirred solution of tert-butyl4-(hydrazinocarbonothioyl)piperazine-1-carboxylate (1.0 g, mmol) in 1,4dioxane (10 mL), hydrochloric acid in dioxane (4 M, 10 mL) was added at0° C. and the mixture was stirred for 4 h at rt. After completion of thereaction, the reaction mixture was concentrated under reduced pressureto get tittle compound. Yield: 87.0% (550 mg, off white). ¹H NMR: (400MHz, DMSO-d₆): δ 11.96 (s, 1H), 9.57 (s, 2H), 3.47-3.45 (m, 4H),3.44-3.15 (m, 4H). LCMS: (Method A) 186.9 (M+H), Rt. 0.549 min, 98.72%(Max).

Intermediate 37: 5-(piperidin-4-yl)-1, 3,4-oxadiazol-2(3H)-onehydrochloride

Step 1: tert-butyl4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

To tert-butyl 4-(hydrazinocarbonyl)piperidine-1-carboxylate (1.0 g,4.112 mmol) in DCM (10 mL), triethylamine (1.7 mL, 12.337 mmol) andcarbonyldiimidazole (2.0 g, 12.337 mmol) were added and the mixture wasstirred for 4 h at rt. After completion of reaction, the reactionmixture was poured into 50 mL of brine solution and extracted withEtOAc. The EtOAc layer was dried over Na₂SO₄ and concentrated underreduced pressure to get crude compound. The resulting crude was purifiedby flash chromatography (Elutant: 1-2% MeOH in DCM) to afford titlecompound. Yield: 55.4% (610 mg, off white). ¹H NMR: (400 MHz, DMSO-d₆) δ12.10 (br, 1H), 3.84-3.92 (m, 2H), 2.80-2.95 (m, 3H), 1.83-1.91 (m, 2H),1.38-1.50 (m, 2H), 1.39 (5, 9H). LCMS: (Method A) 170.2 (M+H), Rt. 2.382min, 94.3% (Max).

Step 2: 5-(piperidin-4-yl)-1, 3,4-oxadiazol-2(3H)-one hydrochloride

To the tert-butyl4-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (520mg, 2.512 mmol) in 1,4 dioxane (5 mL), 4M hydrochloric acid in dioxane(5 mL) was added at 0° C. The reaction mixture was stirred for 4 h atrt. After completion of reaction, the reaction mixture was concentratedto get tittle compound. Yield: 95.0% (311 mg, off white). LCMS: (MethodA) 170.2 (M+H), Rt. 0.610 min, 77.0% (Max).

Intermediate 38:7-(piperazin-1-yl)-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

Step 1: Methyl 2-(2-chloro-5-nitropyridin-4-yl)oxy)acetate

To a stirred solution of 2,4-dichloro-5-nitropyridine (26 mmol, 5 g) andmethyl glycolate (31.2 mmol, 2.41 mL) in DMF at 0° C., sodium hydridewas added (60% in mineral oil, 31.2 mmol, 1.25 g) and the mixture wasstirred at rt overnight. The reaction mixture was quenched with ammoniumchloride solution (30 mL) and extracted with EtOAc (3×50 mL).

The combined organic layer was dried over Na₂SO₄ and concentrated undervacuum. The resulting crude product was purified by columnchromatography affording the title product (yellow solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.93 (s, 1H), 7.71 (s, 1H), 5.23 (s, 2H), 3.74 (s, 3H).LCMS: (Method A) 247.0 (M+H), Rt. 2.436 min, 83.5% (Max).

Step 2: 7-chloro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

To a stirred suspension of methyl2-((2-chloro-5-nitropyridin-4-yl)oxy)acetate (10 mmol, 2.5 g) in ethanol(25 mL), acetic acid (10 mL) and iron powder (50 mmol, 2.8 g) were addedat rt and the mixture was heated to 80° C. for 20 h. The reactionmixture was filtered through celite and concentrated. The resultingproduct was purified by flash chromatography, affording the titleproduct. Yield: 77% (1.4 g, pale brown solid). ¹H NMR (400 MHz,DMSO-d₆): δ 11.03 (s, 1H), 7.84 (s, 1H), 7.15 (s, 1H), 4.75 (s, 2H).LCMS: (Method B) 185 (M+H), Rt. 2.078 min, 98.29% (Max).

Step 3: 7-(piperazin-1-yl)-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

To a stirred solution of methyl2-((2-chloro-5-nitropyridin-4-yl)oxy)acetate (1.0 g 5.43 mmol) in NMP (4mL) was added piperazine (27 mmol, 2.3 g mmol) at rt and the mixture washeated at 150° C. overnight. The completion of the reaction wasconfirmed by TLC. The reaction mixture was evaporated under reducedpressure. The resulting crude mixture was suspended in water (2 mL) andextracted with EtOAc (2×10 mL). The organic layer was dried over Na₂SO₄and concentrated. The resulting product was purified by columnchromatography (yellow solid). LCMS: (Method A) 235.3 (M+H), Rt. 0.516min, 54.4% (Max).

Intermediate 39: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazinehydrochloride

Step 1:(R)—N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide

To a mixture of 1-(benzo[d][1,3]dioxol-5-yl)ethan-1-one (105.7 g, 644.6mmol), (R)-(+)-2-methyl-2-propanesulfinamide (85.79 g, 709 mmol) in THF(1.0 L), titanium(IV) ethoxide (294.06 g, 1289.2 mmol) was added at rtover 30 min and refluxed for 35 h. The reaction was monitored by HPLC.The reaction mixture was cooled to rt and slowly quenched with water(500 mL). The precipitate observed was filtered through celite bed (100g) and washed with EtOAc (2.0 L). The organic layer was washed withwater (500 mL), brine solution (300 mL) and dried over Na₂SO₄. (100 g)and evaporated under vacuum at 50° C. The resulting crude product wascodistilled with toluene (2×500 mL) and used as such for next stepwithout any further purification (164 g, brown liquid). LCMS: (Method A)268.0 (M+H), Rt. 3.87 min, 83.05% (Max).

HPLC: (Method A) Rt. 3.81 min, 57.62% (Max).

Step 2:(R)-N-((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide

To a stirred solution of(R)—N-(1-(benzo[d][1,3]dioxol-5-yl)ethylidene)-2-methylpropane-2-sulfinamide(96 g, 359 mmol) in THF (960 mL), L-Selectride (539 mL, 539 mmol, 1 Msolution in THF) was added under nitrogen atmosphere at −50° C. over 30min and stirred for 1 h. The completion of the reaction was confirmed byTLC. The reaction mixture was quenched with methanol (150 mL), water(750 mL) and stirred overnight at rt. The aqueous layer was extractedwith EtOAc (2×300 mL). The combined organic layer was washed with sat.NH₄Cl (2×250 mL), brine (250 mL), dried over Na₂SO₄ and evaporated undervacuum at 50° C. The resulting crude product (as light brown thick oil)was diluted with pet ether (250 mL) and stirred at −20° C. for 30 min.The resulting precipitate was filtered and washed with pet ether (2×100mL). It was dried under vacuum to give the title compound. Yield: 70.2%(68 g, Off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.89 (s, 1H),6.83-6.77 (m, 2H), 5.99-5.95 (m, 2H), 5.25 (d, J=5.2 Hz, 1H), 4.30 (q,J=6.0 Hz, 1H), 1.39 (d, J=1.6 Hz, 3H), 1.11-1.06 (m, 9H). LCMS: (MethodA) 270.0 (M+H), Rt. 3.66 min, 99.65% (Max). HPLC: (Method A) Rt. 3.62min, 99.69% (Max). Chiral HPLC: (Method C) Rt. 9.71 min, 100%.

Step 3: (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine

To a stirred solution of(R_(S))—N—((S)-1-(benzo[d][1,3]dioxol-5-yl)ethyl)-2-methylpropane-2-sulfinamide(68 g, 252 mmol) in MeOH (680 mL), thionyl chloride (74.3 g, 630 mmol)was added at 0° C. over 15 min and the resulting mixture was stirred atrt for 1 h. The completion of the reaction was confirmed by TLC. Thereaction mixture was concentrated under vacuum at 50° C. The resultingresidue was suspended in EtOAc (300 mL), filtered and washed with EtOAc(150 mL). The product was basified with 30% aqueous ammonia solution(300 mL) and extracted with EtOAc (2×250 mL). The combined organic layerwas washed with brine solution (1×150 mL) and dried over Na₂SO₄. Thesolvent was evaporated at under vacuum to give the title compound.Yield: 92.84% (38.3 g, brown liquid). ¹H NMR (400 MHz, DMSO-d₆): δ 6.95(s, 1H), 6.81-6.77 (m, 2H), 5.95 (s, 2H), 3.90 (q, J=6.56 Hz, 1H), 1.85(s, 2H), 1.19 (m, J=6.56 Hz, 3H). LCMS: (Method A) 149.0 (M-16), Rt.1.65 min, 99.56% (Max). HPLC: (Method A) Rt. 1.60 min, 99.61% (Max).Chiral HPLC: (Method B) Rt 11.11 min, 100%.

Step 4: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine

To a stirred solution of (S)-1-(benzo[d][1,3]dioxol-5-yl)ethan-1-amine(41 g, 248 mmol) in DIPEA (86.6 mL, 496 mmol),N,N-bis(2-chloroethyl)-p-toluene sulfonamide (80.74 g, 273 mmol) wasadded at rt and the resulting mixture was heated at 105° C. overnight.The completion of the reaction was confirmed by TLC and the reactionmixture was diluted with water (1000 mL) and extracted with EtOAc (2×500mL). The combined organic layer was washed with water (200 mL), brinesolution (200 mL) and dried over Na₂SO₄. After evaporation of thesolvent, the resulting crude solid was suspended in pet ether (350 mL)and stirred for 10 min at rt. The suspension was filtered and was washedwith Et₂O (2×200 mL) and dried under vacuum to give the title compound.Yield: 63.2% (61 g, Off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.59(d, J=8.2 Hz, 2H), 7.45 (d, J=8.2 Hz, 2H), 6.81-6.77 (m, 1H), 6.69 (d,J=7.4 Hz, 1H), 5.96 (s, 2H), 3.32 (q, J=7.76 Hz, 1H), 2.81-2.80 (m, 4H),2.42 (s, 3H), 2.36-2.32 (m, 4H), 1.18 (d, J=6.4 Hz, 3H). LCMS: (MethodA) 389.2 (M+H), Rt. 3.40 min, 98.09% (Max). HPLC: (Method A) Rt. 3.30min, 98.69% (Max).

Chiral HPLC: (Method D) Rt. 15.79 min, 100.00%

Step 5: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazinehydrochloride

To a mixture of(S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-tosylpiperazine (61 g, 157mmol) and 4-hydroxy benzoic acid (65.01 g, 471 mmol), HBr in acetic acid(244 mL) was added at 0° C. and the reaction mixture was stirred at rtovernight. The completion of the reaction was confirmed by TLC. Thereaction mixture was diluted with water (400 mL). The precipitate wasfiltered through celite bed and washed with water (200 mL). The aqueousfilterate was washed with EtOAc (4×300 mL) and basified up to pH 11 withNaOH pellet (30 g) at 0° C. (during basification the colour of aqeuouswas converted to light back). The product was extracted with EtOAc(4×300 mL). The combined organic layer was dried over Na₂SO₄ andevaporated under vacuum. The resulting light black oil was diluted in1,4 Dioxane (50 mL) and cooled to 0° C. and 4.5 N HCl solution indioxane (100 mL) was added and stirred for 15 min at rt. The solvent wasevaporated at 45° C. under reduced pressure to get the title compound(pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.11 (s, 1H), 7.32 (s,1H), 7.06-6.99 (m, 2H), 6.07 (s, 2H), 4.55-4.52 (m, 1H), 3.80-3.61 (m,2H), 3.05-2.95 (m, 2H), 2.51-2.50 (m 4H), 1.68 (s, 3H). LCMS: (Method A)235.3 (M+H), Rt. 1.53 min, 95.85% (Max). HPLC: (Method A) Rt. 1.52 min,95.06% (Max). Chiral HPLC: (Method A) Rt. 8.11 min, 100%.

Intermediate 40: (S)-1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine

The hydrochloride salt of1-(1-(benzo[d][1,3]dioxol-5-yl)ethyl)piperazine (20 g) was suspended inNaOH solution (1 M, 150 mL) and extracted with EtOAc (150 mL). The waterlayer was further extracted two times with EtOAc (50 mL). The combinedorganic layers were dried over MgSO₄ and filtered off. After evaporationof the solvent, the title compound was isolated as an oil (10 g). Theaqueous layer was further basified to pH 12 (pH after the extraction wasaround 7-8) by addition of 2 M NaOH solution and further extracted withEtOAc. A second batch of the title compound (5 g) was isolated.

Example 1:6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-3-methylimidazo[1,5-a]pyridine

To a degassed solution of Intermediate 13 (178 mg, 0.77 mmol),Intermediate 19 (125 mg, 0.59 mmol) and sodium tert-butoxide (170 mg,1.77 mmol) in 1,4 dioxane (4 mL), Pd₂(dba)₃ (27 mg, 0.03 mmol) and Xphos(28 mg, 0.05 mmol) were added at rt and the mixture was heated in sealedtube at 100° C. overnight. The reaction mixture was filtered throughcelite and concentrated. The crude mixture was diluted with water (4 mL)and extracted with DCM (2×10 mL). The combined organic layer was driedover Na₂SO₄ and concentrated. The crude product was purified by flashchromatography, followed by preparative HPLC, affording the titleproduct (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.37 (d, J=10.0 Hz,1H), 7.16 (q, J=14.4 Hz, 3H), 6.79-6.70 (m, 3H), 4.51 (t, J=8.4 Hz, 2H),3.49-3.35 (m, 1H), 3.14 (t, J=8.4 Hz, 2H), 3.11-2.83 (m, 4H), 2.67-2.51(m, 4H), 2.50-2.33 (m, 3H), 1.31 (d, J=6.4 Hz, 3H). LCMS: (Method A)363.3 (M+H), Rt. 2.15 min, 97.41% (Max). HPLC: (Method A) Rt 2.32 min,96.88% (Max).

Example 2:6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)isoindolin-1-one

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 4 and Intermediate 35 (brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.42 (s, 1H), 7.38 (d, J=8.4 Hz,1H), 7.20-7.16 (m, 2H), 7.07 (s, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.73 (s,1H), 6.54 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.24 (s, 2H), 3.19-3.10 (m,6H), 2.62-2.55 (m, 2H), 2.49-2.42 (m, 2H), 1.30 (d, J=6.80 Hz, 3H).LCMS: (Method A) 364.2 (M+H), Rt. 2.50 min, 93.23% (Max). HPLC: (MethodA) Rt 2.56 min, 91.88% (Max).

Example3:7-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 4 and Intermediate 38 (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 10.58 (s, 1H), 7.65 (s, 1H),7.15 (d, J=7.2 Hz, 1H), 6.74 (t, J=7.6 Hz, 2H), 6.39 (s, 1H), 4.60-4.53(m, 2H), 3.34-3.32 (m, 2H), 2.68 (s, 7H), 2.48-2.46 (m, 2H), 1.27 (d,J=6.8 Hz, 3H). LCMS: (Method A) 381.2 (M+H), Rt. 2.013 min, 99.2% (Max).HPLC: (Method A) Rt 2.04 min, 99.5% (Max).

Example 4:6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)isoindolin-1-one

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 1 and Intermediate 35 (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (dd, J=1.6, -7.4 Hz, 2H), 8.41(s, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.2 Hz, 1H), 7.92 (dd,J=1.6, 8.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.19 (dd, J=2.0, 8.4 Hz,1H), 7.07 (d, J=2.0 Hz, 1H), 4.23 (s, 2H), 3.77-3.75 (m, 1H), 3.19-3.16(m, 4H), 2.67-2.65 (m, 4H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A)374.2 (M+H), Rt. 1.93 min, 99.2% (Max). HPLC: (Method A) Rt 2.01 min,99.35% (Max).

Example 5: 1-(2-(4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one

The title compound was synthesized according to the procedure describedfor Example 10, starting from Example 7. The resulting crude waspurified by flash chromatography to give the title compound (yellowsolid). ¹H NMR (400 MHz, DMSO-d6): δ 8.18 (s, 1H), 7.14 (d, J=7.6 Hz,1H), 6.75 (d, J=7.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 4.43(s, 2H), 4.43-3.66 (m, 7H), 3.13 (t, J=8.4 Hz, 2H), 2.73 (t, J=6.0 Hz,2H), 2.61-2.59 (m, 2H), 2.34-2.31 (m, 2H), 2.08 (s, 3H), 1.27 (d, J=6.40Hz, 3H). LCMS: (Method A) 408.2 (M+H), Rt. 2.56 min, 97.96% (Max). HPLC:(Method A) Rt. 2.49 min, 97.69% (Max).

Example 6: 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethan-1-one

The title compound was synthesized according to the procedure describedfor Example 10, starting from Example 8. The final product was purifiedby flash chromatography (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.94-8.92 (dd, J=7.2, 2.0 Hz, 2H), 8.18 (s, 1H), 8.09 (d, J=8.8 Hz, 1H),8.00 (s, 1H), 7.92 (dd, J=8.8, 1.6 Hz, 1H), 4.48-4.43 (m, 2H), 3.77-3.75(m, 1H), 3.70-3.69 (m, 6H), 2.73 (t, J=6.0 Hz, 2H), 2.51 (t, J=1.6 Hz,2H), 2.41 (t, J=4.80 Hz, 2H), 2.07 (s, 3H), 1.43 (d, J=6.80 Hz, 3H).LCMS: (Method A) 418.2 (M+H), Rt. 1.94 min, 99.44% (Max). HPLC: (MethodA) Rt. 1.99 min, 99.23% (Max).

Example 7:2-(4-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

The title compound was synthesized according to the procedure describedfor Example 8, starting from Intermediate 13 and Intermediate 17. Yield:65% (0.095 g, pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.05 (s,1H), 7.13 (d, J=7.6 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.70 (s, 1H), 4.49(t, J=8.8 Hz, 2H), 3.75 (s, 2H), 3.63-3.63 (m, 5H), 3.12 (t, J=8.8 Hz,2H), 3.04 (t, J=6.0 Hz, 2H), 2.60 (t, J=5.6 Hz, 2H), 2.45-2.41 (m, 4H),1.26 (d, J=6.8 Hz, 3H).LCMS: (Method A) 366.3 (M+H), Rt. 1.98 min,95.91% (Max). HPLC: (Method A) Rt. 2.021 min, 95.60% (Max).

Example 8: 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-5, 6, 7,8-tetrahydropyrido [4,3-d]pyrimidine

Step 1: Tert-butyl 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-7,8-dihydropyrido [4, 3-d] pyrimidine-6(5H)-carboxylate

To the stirred solution of Intermediate 2 (1.7 g, 6.28 mmol) in dry DMF(15 mL), TEA (2.67 mL, 19.33 mmol) and Intermediate 17 (1.3 g, 4.83mmol) were added at rt and stirred at 80° C. overnight. The reactionmixture was evaporated under vacuum. The resulting crude mixture wasdiluted with EtOAc (30 mL) and washed with water (10 mL), dried overanhydrous Na₂SO₄ and evaporated under vacuum. The resulting crudeproduct was purified by flash chromatography to give title compound.Yield: 36% (0.6 g, Brown thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94(d, J=2.4 Hz, 2H), 8.17 (s, 1H), 7.93-7.90 (m, 3H), 4.34 (s, 2H),3.76-3.74 (m, 5H), 3.57 (t, J=7.6 Hz, 2H), 2.89-2.89 (m, 2H), 2.43-2.41(m, 4H), 1.45 (s, 9H), 1.43 (d, J=11.2 Hz, 3H). LCMS: (Method A) 476.2(M+2), Rt. 3.44 min, 87.38% (Max).

Step 2: 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)-5, 6, 7,8-tetrahydropyrido [4, 3-d] pyrimidine

To the stirred solution of tert-butyl 2-(4-(1-(quinoxalin-6-yl) ethyl)piperazin-1-yl)-7, 8-dihydropyrido [4, 3-d] pyrimidine-6(5H)-carboxylate(0.6 g, 1.26 mmol) in 1,4-dioxane (2 mL), 4M HCl in dioxane (5 mL) wasadded and the mixture was stirred at rt for 2 h. It was evaporated undervacuum. To the resulting crude mixture MeOH (10 mL) was added and thesolution was basified with 10% NaOH solution (2 mL). It was concentratedand the resulting crude mixture was purified by flash chromatography togive title compound. Yield: 78% (0.37 g, brown solid). ¹H NMR (400 MHz,DMSO-d6): δ 8.94-8.92 (m, 2H), 8.10 (s, 1H), 8.01 (d, J=9.6 Hz, 2H),7.93-7.91 (m, 1H), 3.72-3.72 (m, 1H), 3.67-3.65 (m, 6H), 3.33 (s, 1H),2.94 (t, J=6.0 Hz, 2H), 2.68 (t, J=1.6 Hz, 2H), 2.55 (t, J=5.6 Hz, 2H),2.34 (t, J=1.60 Hz, 2H), 1.43 (d, J=6.40 Hz, 3H). LCMS: (Method A) 376.3(M+2), Rt. 1.53 min, 97.74% (Max). HPLC: (Method A) Rt. 1.54 min, 99.50%(Max).

Example 9:6-methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine

To the stirred solution of Example 8 (0.15 g, 0.40 mmol) in1,2-dichloroethane (3 mL), p-formaldehyde (0.024 g, 0.80 mmol) was addedat rt and the mixture was stirred at rt. After 2 h, sodium triacetoxyborohydride (0.25 g, 1.20 mmol) was added and the mixture was stirred atrt overnight. The reaction mixture was diluted with DCM (10 mL) andwashed with water (2 mL), dried over anhydrous Na₂SO₄ and evaporatedunder vacuum. The resulting crude product was purified by flashchromatography affording the title compound (brown solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.94-8.92 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 8.05 (s,1H), 8.00 (s, 1H), 7.92 (d, J=6.8 Hz, 1H), 3.88-3.85 (m, 1H), 3.75 (t,J=6.8 Hz, 4H), 3.32 (t, J=5.2 Hz, 2H), 2.68-2.66 (m, 2H), 2.63 (t,J=12.8 Hz, 2H), 2.54-2.51 (m, 2H), 2.42-2.41 (m, 2H), 2.33 (s, 3H), 1.43(d, J=6.8 Hz, 3H). LCMS: (Method A) 390.2 (M+2), Rt. 1.51 min, 97.08%(Max). HPLC: (Method A) Rt. 1.55 min, 96.75% (Max).

Example 10:1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-oneSGN020616-01

To a stirred solution of Example 15 (150 mg, 0.4 mmol) in DCM, TEA (0.11mL, 0.81 mmol) and acetyl chloride (0.038 mg, 0.48 mmol) were added at0° C. and the mixture was stirred for 2 h at rt. It was quenched withiced water and the two phases were separated. The organic phase waswashed with NaHCO₃ (10 mL), brine (10 mL) and dried over anhydrousNa₂SO₄. After evaporation of the solvent, the crude product was purifiedby MD Autoprep HPLC (Method C), affording the title product (whitesolid). ¹H NMR (400 MHz, DMSO-d₆: δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d,J=7.6 Hz, 1H), 6.71 (s, 1H), 4.53-4.46 (m, 4H), 3.71-3.65 (m, 2H),3.39-3.37 (m, 1H), 3.33-3.30 (m, 4H), 3.13 (t, J=8.4 Hz, 2H), 2.51-2.50(m, 5H), 2.08 (s, 3H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 413.3(M+H), Rt. 2.2 min, 97.8% (Max). HPLC: (Method A) Rt 2.3 min, 98.9%(Max).

Example 11:1-(2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-5(4H)-yl)ethan-1-one

The title compound was synthesized according to the procedure describedfor Example 10, starting from Example 19 (yellow solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.94 (dd, J=2.0, 7.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H),8.00 (s, 1H), 7.91 (dd, J=2.0, 8.6 Hz, 1H), 4.48 (d, J=14.8 Hz, 2H),3.81-3.79 (m, 1H), 3.70-3.65 (m, 2H), 3.40-3.33 (m, 4H), 2.61-2.58 (m,2H), 2.51-2.50 (m, 4H), 2.08 (s, 3H), 1.44 (d, J=6.80 Hz, 3H). LCMS:(Method A) 423.3 (M+H), Rt. 1.81 min, 99.2% (Max). HPLC: (Method A) Rt1.85 min, 98.9% (Max).

Example 12:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Intermediates 6 (0.5 g, 1.61 mmol) in DMF (5mL, 10V), TEA (0.89 mL, 6.4 mmol) and Intermediate 4 (0.44 g, 2.41 mmol)were added at rt and the mixture was stirred at 80° C. for 12 h. It wasconcentrated under vacuum and resulting crude mixture was purified by MDAutoprep HPLC (Method C) to afford titled compound (off white solid). ¹HNMR (400 MHz, DMSO-d6): δ 7.29 (s, 1H), 7.16 (d, J=7.2 Hz, 1H), 6.76 (d,J=7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.46-3.42 (m, 4H),3.38-3.36 (m, 4H), 3.14 (t, J=8.8 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H),2.44-2.43 (m, 2H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (Method A) 358.0(M+H), Rt. 2.324 min, 97.963% (Max). HPLC: (Method A) Rt. 2.279 min,99.224% (Max).

Example 13:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-5-methyl-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

To a stirred solution of Example 12 (0.3 g, 0.78 mmol) in THF (3 mL,10V), NaH (0.125 g, 3.12 mmol) was added at 0° C. and the mixture wasstirred for 1 h. Then Mel (0.22 g, 1.56 mmol) was added at sametemperature and the stirring was continued for 12 h. The reactionmixture was quenched with iced water (3 mL) and extracted with EtOAc(2×10 mL). The combined organic layer was washed with brine, dried overNa₂SO₄ and concentrated under vacuum. After flash chromatograghy, theresulting product was further purified by MD Autoprep HPLC (Method C) toafford titled compound (dark yellow thick oil). ¹H NMR (400 MHz,DMSO-d₆): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s,1H), 4.50 (t, J=8.4 Hz, 2H), 3.49-3.44 (m, 7H), 3.18-3.11 (m, 2H), 2.87(s, 3H), 2.80-2.78 (m, 2H), 2.41-2.39 (m, 4H), 1.27 (d, J=6.8 Hz, 3H).LCMS: (Method A) 399.2 (M+H), Rt. 2.857 min, 97.21% (Max). HPLC: (MethodA) Rt. 2.512 min, 98.36% (Max).

Example 14:5-methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-6,7-dihydrothiazolo[5,4-c]pyridin-4(5H)-one

The title compound was synthesized according to the procedure describedfor Example 13, starting from Intermediates 1 and 6 (dark yellow thickoil). ¹H NMR (400 MHz, DMSO-d6): δ 8.94 (d, J=6.8 Hz, 2H), 8.10 (d,J=8.4 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 3.83 (d, J=6.8 Hz,1H), 3.49-3.48 (m, 6H), 2.87 (s, 3H), 2.79 (t, J=7.2 Hz, 2H), 2.62-2.61(m, 4H), 1.44 (d, J=6.4 Hz, 3H). LCMS: (Method A) 409.2 (M+H), Rt. 1.956min, 99.033% (Max). HPLC: (Method A) Rt. 2.003 min, 99.291% (Max).

Example 15:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

Step 1:2-(4-(1-(2,3-Dihydrobenzofuran-7-yl)ethyl)piperazin-1-yl)-5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To a stirred solution of Intermediate 15 (1.5 g, 3.2 mmol) in DMF (10mL), TEA (1.3 mL, 9.6 mmol) and Intermediate 4 (0.878 g, 4.8 mmol), wereadded at 0-5° C. and the mixture was stirred at 100° C. overnight. Itwas concentrated and EtOAc (30 mL) was added. The resulting solution waswashed with water (20 mL), brine (20 mL) and dried over Na₂SO₄. Afterevaporation of the solvents, the crude product was purified by flashchromatography affording the title product (yellow solid). LCMS: (MethodA) 612.8 (M+H), Rt. 8.6.min, 35.4% (Max).

Step 2:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To a stirred solution of2-(4-(1-(2,3-dihydrobenzofuran-7-yl)ethyl)piperazin-1-yl)-5-trityl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine(0.2 g, 0.32 mmol) in DCM, TFA (20% in DCM, 8 mL) was added at 0° C. andthe mixture was stirred for 2 h at rt. The reaction mixture wasconcentrated and DCM (200 mL) was added. The resulting solution waswashed with NaHCO₃ (10 mL), brine (10 mL), dried over anhydrous Na₂SO₄and concentrated. The crude product was purified by MD Autoprep HPLC(Method C). Yield: 62% (70 mg, Yellow solid). ¹H NMR (400 MHz, DMSO-d₆):δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.51 (t,J=8.8 Hz, 2H), 3.67 (s, 2H), 3.39-3.37 (m, 1H), 3.34-3.29 (m, 4H), 3.14(t, J=8.4 Hz, 2H), 2.90 (t, J=5.6 Hz, 2H), 2.47-2.46 (m, 2H), 2.40-2.30(m, 4H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 371.2 (M+H), Rt. 2.0min, 96.4% (Max). HPLC: (Method A) Rt 1.97 min, 97.8% (Max).

Example 16:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

To a stirred solution of Example 15 (0.15 g, 0.4 mmol) in MeOH, paraformaldehyde (0.36 mg, 1.2 mmol) and sodium cyanoborohydride (0.038 mg,0.6 mmol) were added at 0° C. and the mixture was stirred for 2 h at rt.It was concentrated and DCM was added. The resulting solution was washedwith water (10 mL), brine (10 mL), dried over anhydrous Na₂SO₄.

After evaporation of the solvents, the crude product was purified by MDAutoprep HPLC (Method C), affording the title product (pale brown). ¹HNMR (400 MHz, DMSO-d₆): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz,1H), 6.71 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 3.39-3.37 (m, 4H), 3.34-3.29(m, 4H), 3.14 (t, J=8.4 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H), 2.56 (t, J=1.6Hz, 2H), 2.51-2.50 (m, 2H), 2.33 (s, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS:(Method A) 385.2 (M+H), Rt. 1.96 min, 96.9% (Max). HPLC: (Method A) Rt1.99 min, 96.5% (Max).

Example 17 and 18:(S)-2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridineand(R)-2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

The racemic mixture of Example 15 was separated by chiral preparativeHPLC, using the chiral preparative HPLC (Method X).

The first eluting compound correspond to Example 17 (yellow solid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz,1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.66 (s, 2H), 3.38-3.37 (m,1H), 3.30-3.27 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 2.89 (t, J=5.6 Hz, 2H),2.47-2.45 (m, 2H), 2.40-2.37 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS:(Method A) 371.2 (M+H), Rt. 1.95 min, 97.9% (Max). HPLC: (Method A) Rt1.98 min, 98.8% (Max). CHIRAL HPLC: (Method P) Rt. 7.15 min, 100% (Max).

The second eluting compound correspond to Example 18 (yellow solid). ¹HNMR (400 MHz, DMSO-d₆): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d, J=7.6 Hz,1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.66 (s, 2H), 3.38-3.37 (m,1H), 3.30-3.27 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 2.89 (t, J=6.0 Hz, 2H),2.47-2.45 (m, 2H), 2.40-2.37 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS:(Method A) 371.2 (M+H), Rt. 1.95 min, 99.5% (Max). HPLC: (Method A) Rt1.99 min, 99.4% (Max). CHIRAL HPLC: (Method P) Rt. 20.9 min, 100% (Max).

Example 19:2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

The title compound was synthesized according to the procedure describedfor Example 15, starting from Intermediate 1 and Intermediate 15 (brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (dd, J=2.0, 5.2 Hz, 2H), 8.08(dd, J=2.0, 8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 3.79-3.77(m, 1H), 3.66 (s, 2H), 3.37-3.30 (m, 4H), 2.91 (t, J=5.6 Hz, 2H),2.59-2.56 (m, 2H), 2.56-2.40 (m, 5H), 1.42 (d, J=6.40 Hz, 3H). LCMS:(Method A) 381.2 (M+H), Rt. 1.47 min, 99.5% (Max). HPLC: (Method A) Rt1.52 min, 99.04% (Max).

Example 20:5-Methyl-2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine

The title compound was synthesized according to the procedure describedfor Example 16, starting from Example 19 (white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.94 (dd, J=2.0, 7.0 Hz, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.99(s, 1H), 7.90 (d, J=8.4 Hz, 1H), 3.79-3.78 (m, 1H), 3.39 (s, 2H),3.36-3.30 (m, 4H), 2.66-2.64 (m, 4H), 2.45-2.44 (m, 4H), 2.34 (s, 3H),1.42 (s, 3H). LCMS: (Method A) 395.2 (M+H), Rt. 1.5 min, 98.9% (Max).HPLC: (Method A) Rt 1.52 min, 99.1% (Max).

Example 21:5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2(3H)-one

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 1 and Intermediate 36 (palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.87 (s, 2H), 8.51 (s, 1H),8.12 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 3.74 (d,J=6.0 Hz, 1H), 3.38-3.21 (m, 4H), 2.68-2.66 (m, 2H), 2.56-2.54 (m, 2H),1.50 (d, J=6.0 Hz, 3H). LCMS: (Method A) 343.2 (M+H), Rt. 1.63 min,98.23% (Max). HPLC: (Method A) Rt. 1.69 min, 98.3% (Max).

Example 22:5-(1-(1-(quinoxalin-6-yl)ethylpiperidin-4-yl)-1,3,4-oxadiazol-2(3H)-one

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 1 and Intermediate 37 (darkbrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 8.93 (s, 2H),8.07-7.89 (m, 3H), 3.81 (s, 1H), 2.98 (s, 1H), 2.81 (s, 1H), 2.11-0.00(m, 2H), 1.91-1.83 (m, 2H), 1.61-0.00 (m, 2H), 1.42-0.00 (m, 3H). LCMS:(Method A) 326.3 (M+H), Rt. 1.55 min, 96.75% (Max). HPLC: (Method A) Rt.3.48 min, 96.9%.

Example 23:2-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-4-yl)-5-methyl-1,3,4-oxadiazole

The title compound was synthesized according to the procedure describedfor Example 24, starting from Intermediate 4 (dark yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.13 (d, J=7.2 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H),6.69 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.40-3.37 (m, 1H), 3.12 (t, J=8.8Hz, 2H), 2.93-2.90 (m, 1H), 2.80-2.74 (m, 2H), 2.43 (s, 3H), 2.04-1.88(m, 4H), 1.69-1.59 (m, 2H), 1.25 (d, J=6.80 Hz, 3H). LCMS: (Method A)314.2 (M+1) Rt.

2.263 min, 95.868% (Max). HPLC: (Method A) Rt. 2.220 min, 94.865% (Max).

Example 24:2-methyl-5-(1-(1-(quinoxalin-6-yl)ethylpiperidin-4-yl)-1,3,4-oxadiazole

To a stirred solution of 2-methyl-5-(piperidin-4-yl)-1,3,4-oxadiazolehydrochloride (0.3 g, 1.47 mmol, ABCR) in DMF (3 mL, 10V), cooled to 0°C., TEA (0.82 mL, 5.89 mmol) followed by Intermediate 1 (0.57 g, 2.94mmol) were added and the mixture was stirred at 80° C. for 12 h. It wasthen concentrated. Water (3 mL) was added and was extracted with EtOAc(2×10 mL). The combined organic layer was washed with brine (5 mL) anddried over Na₂SO₄. After evaporation of the solvents, the resultingcrude product was purified by flash chromatography to afford titledcompound (dark yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (d,J=1.6 Hz, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.98 (s,1H), 7.91 (d, J=8.8 Hz, 1H), 3.82-3.81 (m, 1H), 3.00-2.97 (m, 1H),2.86-2.84 (m, 2H), 2.44 (s, 3H), 2.18-2.16 (m, 2H), 2.00-1.97 (m, 2H),1.78-1.74 (m, 2H), 1.43 (d, J=6.80 Hz, 3H). LCMS: (Method A) 324.2 (M+1)Rt. 1.624 min, 97.172% (Max). HPLC: (Method A) Rt. 1.665 min, 97.713%(Max).

Example 25:N-(1-(1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-4-yl)-1H-pyrazol-4-yl)acetamide

To a stirred solution of Intermediate 11 (0.25 g, 1.2 mmol) in DMF (10mL), TEA (0.5 mL, 3.6 mmol) and Intermediate 4 (0.22 g, 1.2 mmol) wereadded at 0-5° C. The reaction mixture was stirred at 100° C. overnight.The completion of the reaction was confirmed by TLC. The reactionmixture was evaporated at 50° C. under reduced pressure and theresulting crude mixture was diluted with EtOAc (30 mL). The organiclayer was washed with water (10 mL), brine (10 mL) and dried overNa₂SO₄. After evaporation of the solvents, the crude product waspurified by flash chromatography (5-8% MeOH in DCM) to give the titlecompound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.88 (s, 1H), 7.83(s, 1H), 7.38 (s, 1H), 7.16-6.71 (m, 3H), 4.55-4.49 (m, 2H), 4.12-3.99(m, 1H), 3.43-3.41 (m, 1H), 3.16-3.12 (m, 2H), 3.11-3.01 (m, 1H),2.84-2.82 (m, 1H), 2.33-1.80 (m, 9H), 1.26 (d, J=5.20 Hz, 3H). LCMS:(Method A) 355.2 (M+H), Rt. 2.22 min, 97.98% (Max). HPLC: (Method A),Rt. 2.26 min, 96.08% (Max).

Example 26:N-((1-(1-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperidin-4-yl)-1H-pyrazol-4-yl)methyl)acetamide

The title compound was synthesized according to the procedure describedfor Example 112, starting from Example 33. Yield: 62.08% (35 mg,colorless solid thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.06 (d, J=4.4Hz, 1H), 7.62 (s, 1H), 7.31 (s, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.76 (d,J=7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.06-4.04 (m, 3H),3.43-3.41 (m, 1H), 3.16-3.12 (m, 2H), 3.03 (d, J=10.80 Hz, 1H), 2.84 (d,J=9.60 Hz, 1H), 2.08-2.02 (m, 1H), 1.97-1.87 (m, 5H), 1.80 (s, 3H), 1.3(t, J=6.8 Hz, 3H). LCMS: (Method A) 369.2 (M+H), Rt. 2.161 min, 99.71%(Max). HPLC: (Method A), Rt. 2.204 min, 98.24% (Max).

Example 27:N-(1-(1-(1-(quinoxalin-6-yl)ethyl)piperidin-4-yl)-1H-pyrazol-4-yl)acetamide

To a stirred solution of Intermediate 11 (0.5 g, 2.4 mmol) in DMF (10mL), TEA (1.0 mL, 7.2 mmol) and Intermediate 1 (0.46 g, 2.4 mmol) wereadded at 0-5° C. The reaction mixture was stirred at 100° C. overnight.The completion of the reaction was confirmed by TLC. The reactionmixture was evaporated at 50° C. under reduced pressure and diluted withEtOAc (30 mL). The organic layer was washed with water (10 mL), brine(10 mL) and dried over Na₂SO₄. After evaporation of the solvents, thecrude product was purified by flash chromatography (5-8% MeOH in DCM) togive the title compound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ9.88 (s, 1H), 8.93 (dd, J=7.2, 1.6 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00(s, 1H), 7.93 (dd, J=8.8, 1.6 Hz, 1H), 7.84 (s, 1H), 7.38 (s, 1H),4.12-4.04 (m, 1H), 3.84-3.83 (m, 1H), 3.09-3.06 (m, 1H), 2.90-2.87 (m,1H), 2.14-2.12 (m, 2H), 1.95 (s, 3H), 1.90-1.88 (m, 4H), 1.44 (d, J=6.80Hz, 3H). LCMS: (Method A) 365.2 (M+H), Rt. 1.73 min, 97.63% (Max). HPLC:(Method A), Rt. 1.74 min, 97.46% (Max).

Example 28: (1-(1-(1-(2, 3-dihydrobenzofuran-6-yl) ethyl)piperidin-4-yl)-1H-pyrazol-4-yl) methanol

To a stirred solution of Example 32 (0.4 g, 1.08 mmol) in dry THF: MeOHmixture (4:1, 10 mL), lithium borohydride (0.81 mL, 1.62 mmol, 2M inTHF) was added at 0° C. and reaction was stirred at rt for 10 h. Thereaction mixture was quenched with ice cooled water (10 mL) andextracted with EtOAc (25 mL). The organic layer was washed with brine (4mL), dried over anhydrous Na₂SO₄ and concentrated. The resulting crudeproduct was purified by flash chromatography to afford the titlecompound. Yield: 56.4% (0.2 g, off white solid). ¹H NMR (400 MHz,DMSO-d6): δ 7.62 (s, 1H), 7.33 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d,J=7.2 Hz, 1H), 6.72 (s, 1H), 4.76 (t, J=5.2 Hz, 1H), 4.51 (t, J=8.4 Hz,2H), 4.32 (d, J=5.6 Hz, 2H), 3.99 (q, J=6.8 Hz, 1H), 3.42 (d, J=6.4 Hz,1H), 3.14 (t, J=8.4 Hz, 2H), 3.03 (d, J=10.80 Hz, 1H), 2.84 (d, J=10.0Hz, 1H), 2.08-2.02 (m, 1H), 1.97-1.81 (m, 5H), 1.3 (d, J=6.8 Hz, 3H).LCMS: (Method A) 328.3 (M+H), Rt. 2.14 min, 96.83% (Max). HPLC: (MethodA) Rt. 2.14 min, 98.26% (Max).

Example 29:1-(1-(2,3-Dihydrobenzofuran-6-yl)ethyl)-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine

To a stirred solution of4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine hydrochloride (0.25 g,0.98 mmol, Anichem) in dry MeCN (5 mL), TEA (0.4 mL, 2.94 mmol) andIntermediate 31 (0.27 g, 1.47 mmol) were added at rt. The reactionmixture was stirred at 60° C. for 14 h. Then the reaction mixture wascooled to rt and partitioned between water (5 mL) and EtOAc (60 mL). Theorganic layer was dried over anhydrous Na2SO4 and concentrated. Theresulting crude product was purified by MD Autoprep HPLC (Method C)(yellow thick oil). ¹H NMR (400 MHz, MeOD): δ 8.15 (s, 1H), 7.77 (s,1H), 7.22 (d, J=7.2 Hz, 1H), 6.86 (d, J=7.2 Hz, 1H), 6.81 (s, 1H), 4.57(t, J=8.4 Hz, 2H), 4.31-4.30 (m, 1H), 3.81-3.80 (m, 1H), 3.44-3.43 (m,1H), 3.21 (t, J=8.8 Hz, 2H), 3.21-3.19 (m, 1H), 2.50-2.49 (m, 2H),2.22-2.13 (m, 4H), 1.53 (d, J=6.0 Hz, 3H).

LCMS: (Method A) 366.3 (M+H), Rt. 3.36 min, 97.15% (Max). HPLC: (MethodA) Rt. 3.31 min, 95.61% (Max).

Example 30:1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-4-(4-fluoro-1H-pyrazol-1-yl)piperidine

The title compound was synthesized according to the procedure describedfor Example 29, starting from Intermediate 31 and 4-fluoro-1H-pyrazole.The crude product was purified by MD auto prep (Method B) to get thetitle compound (brown thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.92 (d,J=4.4 Hz, 1H), 7.42 (d, J=4.0 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.76-6.71(m, 2H), 4.50 (t, J=8.4 Hz, 2H), 3.95 (s, 1H), 3.42-3.40 (m, 1H),3.16-3.11 (m, 2H), 3.04-3.02 (m, 1H), 2.84-2.81 (m, 1H), 2.04 (t, J=9.60Hz, 1H), 1.94-1.83 (m, 4H), 1.80-1.77 (m, 1H), 1.27 (d, J=6.40 Hz, 3H).LCMS: (Method A) 316.2 (M+H), Rt. 2.79 min, 98.82% (Max). HPLC: (MethodA), Rt. 2.77 min, 98.59% (Max).

Example 31:6-(1-(4-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)piperazin-1-yl)ethyl)quinoxaline

Step 1: tert-Butyl4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate

To a stirred suspension of 4-(trifluoromethyl)-1H-pyrazole (0.4 g, 2.93mmol) in dry DMF (8 mL), Cs₂CO₃ (1.91 g, 5.87 mmol) and tert-butyl4-((methylsulfonyl)-oxy) piperidine-1-carboxylate (obtained as describedin Step 1 of Intermediate 10, 1.23 g, 5.87 mmol) were added at 0° C. Thereaction mixture was stirred at 80° C. overnight, and the reactionmixture was diluted with water (10 mL). The product was extracted withEtOAc (2×10 mL). The combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under vacuum. The crude product was purified byflash chromatography on silica gel (230-400 mesh) to afford the titlecompound. Yield: 73% (0.69 g, pale brown solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.71 (s, 1H), 7.90 (s, 1H), 4.44 (q, J=7.6 Hz, 1H),4.04-4.06 (m, 2H), 3.10-2.69 (m, 2H), 2.02-2.08 (d, 2H), 1.84-1.75 (m,2H), 1.42 (s, 9H). LCMS: (Method A) 264.2 (M-56), Rt. 4.82 min, 91.18%(Max).

Step 2: 4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine hydrochloride

To a stirred solution of tert-butyl4-(4-(trifluoromethyl)-1H-pyrazol-1-yl) piperidine-1-carboxylate (0.68g, 2.12 mmol) in dry dioxane (2 mL), HCl in dioxane (5 mL, 4 N) wasadded and the reaction mixture was stirred at rt for 3 h. The reactionmixture was concentrated under vacuum and the resulting crude productwas suspended in diethyl ether (15 mL) and filtered, affording the titlecompound. Yield: 94% (0.51 g, off white solid).LCMS: (Method A) 220.2(M+H), Rt. 2.29 min, 87.95% (Max).

Step 3:6-(1-(4-(4-(Trifluoromethyl)-1H-pyrazol-1-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)piperidine hydrochloride (0.3 g,1.17 mmol) in DMF (6 mL), TEA (0.5 mL, 3.52 mmol) and Intermediate 1(0.27 g, 1.41 mmol) were added at 0° C. The reaction mixture was stirredat 80° C. for 16 h. The completion of the reaction was monitored by TLC.The reaction mixture was evaporated under reduced pressure and dilutedwith EtOAc (10 mL). The organic layer was washed with water (5 mL),brine solution (5 mL) and dried over Na₂SO₄. After evaporation of thesolvents, the crude product was purified by flash chromatography onsilica gel (230-400 mesh) using 55-60% EtOAc in pet ether as eluent,affording the title compound (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 9.01-8.82 (m, 2H), 8.44 (s, 1H), 8.09 (d, J=8.8 Hz, 1H),8.01 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.88 (s, 1H), 4.31-4.07 (m, 1H),3.86 (d, J=6.4 Hz, 1H), 3.10-3.12 (m, 1H), 2.92-2.94 (m, 1H), 2.16-2.18(m, 2H), 2.03-1.99 (m, 4H), 1.45 (d, J=6.40 Hz, 3H). LCMS: (Method A)376.3 (M+H), Rt. 2.79 min, 98.0% (Max). HPLC: (Method A) Rt 2.86 min,97.1% (Max).

Example 32: Ethyl 1-(1-(1-(2, 3-dihydrobenzofuran-6-yl) ethyl)piperidin-4-yl)-1H-pyrazole-4-carboxylate

To a stirred solution of Intermediate 10 (2 g, 7.70 mmol) in dry DMF (20mL), TEA (3.2 mL, 23.10 mmol) and Intermediate 4 (1.54 g, 8.47 mmol)were added. The reaction mixture was stirred at 60° C. overnight. Aftercooling down the mixture at rt, the solvent was evaporated. Resultingcrude mixture was diluted with EtOAc (50 mL) and washed with water (20mL). The organic layer was dried over anhydrous Na₂SO₄ and concentrated.The crude product was purified by flash chromatography affording thetitle compound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.33 (s,1H), 7.85 (s, 1H), 7.15 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72(s, 1H), 4.51 (t, J=8.8 Hz, 2H), 4.20 (q, J=7.2 Hz, 2H), 4.14-4.10 (m,1H), 3.46 (q, J=6.8 Hz, 1H), 3.14 (t, J=8.4 Hz, 2H), 3.03-3.06 (m, 1H),2.85-2.87 (m, 1H), 2.08-2.02 (m, 1H), 1.98-1.77 (m, 5H), 1.36-1.24 (m,6H). LCMS: (Method A) 370.2 (M+H), Rt. 2.95 min, 97.6% (Max). HPLC:(Method A), Rt. 3.05 min, 97.08% (Max).

Example 33:(1-(1-(1-(2,3-dihydrobenzofuran-5-yl)ethyl)piperidine-4-yl)-1H-pyrazol-4-yl)methanamine

The title compound was synthesized according to the procedure describedfor Example 126, starting from Example 28 (colorless solid). ¹H NMR (400MHz, DMSO-d6): δ 7.57 (s, 1H), 7.30 (s, 1H), 7.14 (d, J=7.2 Hz, 1H),6.75 (dd, J=7.6, 1.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.96(br s, 1H), 3.53 (s, 2H), 3.13 (t, J=8.8 Hz, 2H), 3.03-3.00 (m, 1H),2.82-2.81 (m, 1H), 2.04-2.03 (m, 1H), 1.96-1.77 (m, 6H), 1.26 (d, J=6.80Hz, 3H). LCMS: (Method A) 327.0 (M+H), Rt. 4.26 min, 96.2% (Max).

Example 34:1-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)-4-(4-(methylsulfonyl)-1H-pyrazol-1-yl)piperidine

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 4 and Intermediate 21 (paleyellow thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.43 (s, 1H), 7.90 (s,1H), 7.14 (d, J=7.6 Hz, 1H), 6.76-6.71 (m, 2H), 4.50-4.48 (m, 2H), 4.16(t, J=10.8 Hz, 1H), 3.46-3.43 (m, 1H), 3.17-3.11 (m, 5H), 3.02 (d,J=10.8 Hz, 1H), 2.85 (d, J=11.2 Hz, 1H), 2.08-1.83 (m, 6H), 1.27 (d,J=6.80 Hz, 3H). LCMS: (Method A) 376.2 (M+H), Rt. 2.40 min, 97.18%(Max). HPLC: (Method A) Rt. 2.40 min, 97.83% (Max).

Example 35:1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-ol

Step 1:3-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6-iodopyridazine

To a stirred solution of Intermediate 13 (700 mg, 2.3 mmol) in DMF (10mL), TEA (929 mg, 9.2 mmol) and 3-chloro-6-iodopyridazine (826 mg, 3.4mmol) were added at rt and the resulting mixture was heated at 60° C.overnight. Completion of the reaction was monitored by TLC. Reactionmixture was evaporated. The resulting crude product was triturated withDCM (15 mL) and filtered. The solid was dried under reduced pressure,affording the title compound (off white solid). LCMS: (Method A) 437.3(M+H), Rt. 2.71 min, 79.38% (Max).

Step 2:1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-one

The title compound was prepared according to the procedure described forExample 36, step 1, starting from3-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6-iodopyridazine.The crude product was purified by flash chromatography (eluent: 50%EtOAc in pet ether), affording the title compound that was directly usedin the next step. (pale brown oil). LCMS: (Method A) 353.2 (M+H), Rt.2.51 min, 23.74% (Max).

Step 3:1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-ol

The title compound was prepared according to the procedure described forExample 36, step 2, starting from1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-one.The crude was purified by flash chromatography (elutant: 6% MeOH inDCM), affording the title product (beige solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.42 (d, J=9.6 Hz, 1H), 7.22 (d, J=9.6 Hz, 1H), 7.14 (d,J=7.6 Hz, 1H), 6.77-6.71 (m, 2H), 5.32 (d, J=4.8 Hz, 1H), 4.81-4.78 (m,1H), 4.49 (t, J=8.8 Hz, 2H), 3.51-3.35 (m, 5H), 3.12 (t, J=8.4 Hz, 2H),2.66-2.32 (m, 4H), 1.34-1.23 (m, 6H). LCMS: (Method A) 355.2 (M+H), Rt.1.93 min, 96.62% (Max). HPLC: (Method A) Rt 1.93 min, 97.83% (Max).

Example 36:1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-ol

Step 1:1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-one

A stirred solution of Example 43 (500 mg, 1.12 mmol) in dry toluene wasdegassed for 15 min with nitrogen. 1-ethoxy vinyl tributyltin (450 mg,1.23 mmol) and bis(triphenylphosphine)palladium(II) dichloride (80 mg,0.12 mmol) were added at rt. The reaction mixture was stirred forovernight at 90° C. It was cooled to rt and filtered through celite. Thefiltrate was concentrated under vacuum and HCl solution (50 mL, 6N) wasadded. The mixture was stirred 1 h at rt and was neutralized with asaturated solution of NaHCO₃. It was extracted with DCM (100 mL), theorganic layer was dried over anhydrous Na₂SO₄ and concentrated. Thecrude product was purified by flash chromatography to afford the titlecompound (pale brown solid). LCMS: (Method A) 173.0 (M+H), Rt. 2.20 min,95.3% (Max).

Step 2:1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-ol

To a stirred solution of1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3-yl)ethan-1-one(100 mg, 0.21 mmol) in dry MeOH (2 mL), sodium borohydride (15 mg, 0.41mmol, spectrochem) was added portion wise at 0° C. and the resultingmixture was stirred for 1 h. It was concentrated under vacuum. Theresulting residue was dissolved in DCM (20 mL), washed with brine (5mL), dried over Na₂SO₄ and concentrated. The crude product was purifiedby MD Autoprep HPLC (Method D) to afford the titled compound (brownthick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (dd, J=7.2, 1.6 Hz, 2H),8.10 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.44 (d,J=9.6 Hz, 1H), 7.25 (d, J=9.2 Hz, 1H), 5.34 (d, J=4.8 Hz, 1H), 4.80 (t,J=4.8 Hz, 1H), 3.78 (d, J=6.4 Hz, 1H), 3.55-3.51 (m, 4H), 2.64-2.61 (m,2H), 2.51-2.33 (m, 2H), 1.45 (d, J=6.80 Hz, 3H), 1.35 (d, J=6.8 Hz, 3H).LCMS: (Method A) 365.2 (M+H), Rt. 1.43 min, 99.32% (Max). HPLC: (MethodA) Rt. 1.46 min, 98.77% (Max).

Example 37:(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanol

The title compound was synthesized according to the procedure describedfor Example 113, starting from Example 120 (brown solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.93 (d, J=6.4 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00(s, 1H), 7.90 (d, J=8.8 Hz, 1H), 4.56 (d, J=38.4 Hz, 2H), 3.89-3.75 (m,1H), 3.50-3.38 (m, 4H), 2.70-2.65 (m, 2H), 2.49-2.42 (m, 2H), 1.43 (d,J=6.4 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 1.50 min, 99.4% (Max).HPLC: (Method A) Rt 1.52 min, 99.30% (Max).

Example 38:(S)-6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3(2H)-one or(R)-6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridazin-3(2H)-one

The racemic mixture of Example 39 was separated by chiral preparativeHPLC, using the chiral preparative HPLC (Method Q).

The first eluting compound correspond to Example 38. Yield: 28% (14.32mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 8.93(d, J=6.8 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.89 (d, J=8.8Hz, 1H), 7.45 (d, J=10.4 Hz, 1H), 6.74 (d, J=10.0 Hz, 1H), 3.79-3.71 (m,1H), 3.18-3.16 (m, 4H), 2.61-2.59 (m, 4H), 1.43 (d, J=6.40 Hz, 3H).LCMS: (Method A) 337.2 (M+H), Rt. 1.463 min, 99.315% (Max). HPLC:(Method A) Rt. 1.549 min, 98.517% (Max). CHIRAL HPLC: (Method P) Rt.11.173 min, 99.708% (Max).

Second eluting compound: Yield: 28% (14.17 mg, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 12.06 (s, 1H), 8.93 (d, J=5.6 Hz, 2H), 8.08 (d,J=8.4 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 7.45 (d, J=10.4 Hz,1H), 6.74 (d, J=11.2 Hz, 1H), 3.76-3.74 (m, 1H), 3.19-3.16 (m, 4H),2.60-2.57 (m, 4H), 1.43 (d, J=7.20 Hz, 3H). LCMS: (Method A) 337.2(M+H), Rt. 1.462 min, 99.692% (Max). HPLC: (Method A) Rt. 1.554 min,99.192% (Max). CHIRAL HPLC: (Method P) Rt. 17.953 min, 99.333% (Max).

Example 39:2-amino-1-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)ethan-1-one

Step 1: 6-(1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of Intermediate 2 (0.4 g, 1.43 mmol, IS00537-008)in THF (8 mL, 20 V), TEA (0.598 mL, 4.3 mmol) and 3,6-dichloropyridazine(0.427 g, 2.86 mmol) were added at rt and the mixture was stirred at 70°C. for 12 h. It was evaporated under vacuum. Water (5 mL) was added tothe resulting crude mixture and was extracted with EtOAc (2×15 mL). Thecombined EtOAc layer was washed with brine and dried over Na₂SO₄concentrated under vacuum. The crude product was purified by flashchromatography to afford title compound (yellow thick oil). ¹H NMR (400MHz, DMSO-d6): δ 300 MHz, DMSO-d6: δ 8.94 (d, J=3.6 Hz, 2H), 8.11-8.08(m, 3H), 7.52 (dd, J=2.7, 9.6 Hz, 1H), 7.35 (d, J=9.6 Hz, 1H), 3.80-3.78(m, 1H), 3.58-3.44 (m, 4H), 2.73-2.59 (m, 4H), 1.45 (d, J=6.6 Hz, 3H).LCMS: (Method A) 355.2 (M+H), Rt. 1.989 min, 93.235% (Max).

Step 2:2-amino-1-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)ethan-1-one

To a stirred solution of6-(1-(4-(6-chloropyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline in AcOH(2.3 mL), NaOAc (0.106 g, 1.29 mmol) was added and the mixture wasstirred at 200° C. in microwave reactor for 10 min. Reaction mixture wasconcentrated under vacuum. 10% MeOH in THF (3 mL) and KOH (0.072 g, 1.29mmol) were added and the mixture was refluxed for 1 h. After evaporationof the solvents, the crude product was purified by flash chromatographyto afford the title product (brown thick oil). ¹H NMR (400 MHz,DMSO-d₆): δ 12.06 (s, 1H), 8.94 (q, J=1.6 Hz, 2H), 8.09 (d, J=8.8 Hz,1H), 8.00 (d, J=1.6 Hz, 1H), 7.91 (q, J=2.0 Hz, 1H), 7.46 (d, J=10.0 Hz,1H), 6.76 (d, J=10.0 Hz, 1H), 3.77-3.76 (m, 1H), 3.19 (t, J=5.2 Hz, 4H),2.56-2.55 (m, 4H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 337.0(M+H), Rt. 1.540 min, 96.804% (Max). HPLC: (Method A) Rt 1.509 min,99.272% (Max).

Example 40:3-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6-(trifluoromethyl)pyridazineSGN020581-01-00501-018N01:

To a stirred solution of Intermediate 13 (250 mg, 0.81 mmol), in DMF (3mL), TEA (330 mg, 3.26 mmol) and 3-chloro-6-(trifluoromethyl)pyridazine(224 mg, 1.2 mmol) were added at rt. The resulting mixture was heated at85° C. overnight. Completion of the reaction was monitored by TLC.Reaction mixture was evaporated. Water (10 mL) was added and extractedwith EtOAc (2×30 mL). The combined organic layer was washed with water(10 mL), brine (10 mL), dried over Na₂SO₄ and evaporated. The crudeproduct was purified by flash chromatography (elutant: 2-3% MeOH in DCM)to afford the title product (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 7.77 (d, J=9.6 Hz, 1H), 7.35 (d, J=9.6 Hz, 1H), 7.15 (d,J=7.6 Hz, 1H), 6.77-6.73 (m, 2H), 4.50 (t, J=8.4 Hz, 2H), 3.68 (t, J=5.2Hz, 4H), 3.39-3.32 (m, 1H), 3.13 (t, J=8.4 Hz, 2H), 2.44-2.39 (m, 4H),1.29 (d, J=6.8 Hz, 3H). LCMS: (Method A) 379.2 (M+H), Rt. 3.06 min,95.18% (Max). HPLC: (Method A) Rt. 3.12 min, 98.21% (Max).

Example 41:6-(1-(4-(6-Fluoropyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of Intermediate 2 (0.2 g, 0.8 mmol) in dry DMF (5mL), TEA (0.36 ml, 2.85 mmol) and 3,6-difluropyridazine (0.19 g, 1.90mmol) were added at rt and the reaction mixture was stirred at 90° C.overnight. The resulting reaction mixture was cooled to rt and DMF wasevaporated under reduced pressure. To the resulting crude product, water(20 mL) was added and product was extracted with EtOAc (2×30 mL). Theorganic layer was dried over Na₂SO₄ and concentrated. The crude productwas purified by flash chromatography to afford the title compound (palebrown thick oil). ¹H NMR (400 MHz, CDCl₃): δ 8.12 (d, J=8.8 Hz, 1H),8.05 (d, J=1.6 Hz, 1H), 7.92 (dd, J=8.6, 1.6 Hz, 1H), 7.06 (dd, J=9.6,6.0 Hz, 1H), 7.00 (dd, J=7.4, 3.2 Hz, 1H), 3.75-3.68 (m, 1H), 3.67-3.56(m, 4H), 2.76-2.70 (m, 2H), 2.62-2.57 (m, 2H), 1.52 (d, J=6.8 Hz, 3H).LCMS: (Method A) 339.2 (M+H), Rt. 1.77 min, 98.68% (Max). HPLC: (MethodA) Rt 1.80 min, 97.59% (Max).

Example 42:6-(1-(4-(6-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of Intermediate 2 (0.2 g, 0.8 mmol) in dry DMF (5mL), TEA (0.36 ml, 2.85 mmol) and 2-chloro-5(trifluoromethyl) pyridazine(0.19 g, 1.90 mmol) were added at rt and the reaction mixture wasstirred at 90° C. overnight. The resulting reaction mixture was cooledto rt and DMF was evaporated under reduced pressure. To the resultingcrude product, water (20 mL) was added and the product was extractedwith EtOAc (2×30 mL). The organic layer was dried over Na₂SO₄ andconcentrated. This product was purified by flash chromatography toafford the title compound (off white solid). ¹H NMR (400 MHz, CDCl₃): δ8.87 (s, 2H), 8.14 (d, J=8.8 Hz, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.47(d, J=9.6 Hz, 1H), 6.90 (d, J=9.6 Hz, 1H), 3.80-3.82 (m, 5H), 2.68-2.70(m, 1H), 1.54-1.52 (br s, 6.8 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt.2.50 min, 99.68% (Max). HPLC: (Method A) Rt. 2.53 min, 98.79% (Max).

Example 43:6-(1-(4-(6-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

To a stirred solution of Intermediate 2 (0.25 g, 0.8 mmol) in dry DMF (5mL), TEA (0.36 ml, 2.85 mmol) and 3-chloro-6-iodopyridazine (0.123 g,0.99 mmol) were added at rt and the reaction mixture was stirred at 90°C. overnight. The resulting reaction mixture was cooled to rt and DMFwas evaporated under reduced pressure. To the resulting crude mixture,water (20 mL) was added and the product was extracted with EtOAc (2×30mL). The resulting organic layer was dried over Na₂SO₄ and concentrated.This crude product was purified by flash column chromatography to affordthe title compound (off white solid). ¹H NMR (400 MHz, CDCl₃): δ8.86-8.84 (m, 2H), 8.11 (d, J=8.8 Hz, 1H), 8.03 (d, J=2.0 Hz, 1H), 7.90(dd, J=8.8, 2.0 Hz, 1H), 7.45 (d, J=9.6 Hz, 1H), 6.60 (d, J=9.6 Hz, 1H),3.65-3.58 (m, 5H), 2.73-2.67 (m, 2H), 2.59-2.54 (m, 2H), 1.51 (d, J=6.8Hz, 3H). LCMS: (Method A) 447.0 (M+H), Rt. 2.13 min, 99.59% (Max). HPLC:(Method A) Rt. 2.16 min, 98.99% (Max).

Example 44:6-(1-(4-(6-Methylpyridazin-3-yl)piperazin-1-yl)ethyl)quinoxaline

The stirred solution of Example 43 (100 mg, 0.22 mmol) in dry toluenewas degassed for 15 min with nitrogen. Tetramethyl tin (79.0 mg, 0.44mmol) and bis(triphenylphosphine)palladium dichloride (14 mg, 0.02 mmol)were added at rt and the resulting mixture was stirred overnight at 90°C. The reaction mixture was cooled to rt and filtered through celite.This filtrate was concentrated and an aqueous solution of HCl (6 N, 50mL) was added. The resulting mixture was stirred for 1 h at rt and wasneutralized with a saturated solution of NaHCO₃. It was extracted withDCM (100 mL). The organic layer was dried over anhydrous Na₂SO₄ andconcentrated. The crude was purified by flash chromatography to affordthe title compound (brown thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94(d, J=5.2 Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 8.02 (s, 1H), 7.92 (t, J=6.8Hz, 1H), 7.26 (d, J=9.2 Hz, 1H), 7.17 (d, J=9.6 Hz, 1H), 3.88 (d, J=15.8Hz, 1H), 3.50 (br s, 4H), 2.60 (br s, 4H), 2.41 (s, 3H), 1.45 (d, J=5.60Hz, 3H). LCMS: (Method A) 335.2 (M+H), Rt. 1.43 min, 96.15% (Max). HPLC:(Method A) Rt. 1.42 min, 96.07% (Max).

Example 45:3-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-6-(methylsulfonyl)pyridazine

To a stirred solution of Intermediate 13 (150 mg, 0.49 mmol), TEA (198mg, 1.96 mmol) in MeCN (5 mL), 3-chloro-6-(methylsulfonyl)pyridazine(142 mg, 0.73 mmol) was added at rt and the resulting mixture wasstirred overnight at rt. Completion of the reaction was monitored byTLC. Reaction mass was evaporated. Water (10 mL) was added and wasextracted with EtOAc (2×30 mL). The combined organic layer was washedwith water (10 mL), brine solution (10 mL), dried over Na₂SO₄ andevaporated. The crude product was purified by flash chromatography(elutant: 75% EtOAc in pet ether) and further purified by MD AutoprepHPLC (Method C) to afford the title product (off white solid). ¹H NMR(400 MHz, DMSO-d6): δ 7.81 (d, J=9.6 Hz, 1H), 7.36 (d, J=9.6 Hz, 1H),7.15 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.6 Hz, 1H), 6.72 (s, 1H), 4.50 (t,J=8.4 Hz, 2H), 3.72-3.70 (m, 4H), 3.39-3.38 (m, 1H), 3.28 (s, 3H), 3.13(t, J=9.2 Hz, 2H), 2.44-2.32 (m, 4H), 1.29 (d, J=6.80 Hz, 3H). LCMS:(Method A) 389.2 (M+H), Rt. 2.35 min, 97.79% (Max). HPLC: (Method A) Rt.2.37 min, 97.46% (Max).

Example 46:N-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)acetamide

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 2 andN-(6-bromopyridin-2-yl)acetamide (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 9.89 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.93 (d, J=1.6 Hz,1H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.47(d, J=8.0 Hz, 1H), 7.32 (s, 1H), 6.44 (d, J=8.0 Hz, 1H), 3.77-3.72 (m,1H), 3.51-3.45 (m, 4H), 2.58-2.53 (m, 2H), 2.49-2.44 (m, 2H), 2.04 (s,3H), 1.44 (d, J=6.80 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 1.998min, 95.756% (Max).

HPLC: (Method A) Rt. 2.057 min, 95.464% (Max).

Example 47:1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-ol

Step 1:1-(5-bromopyridin-2-yl)-4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine

To a stirred solution of 2-chloro-5-bromopyridine (5.4 g, 19.7 mmol) indry DMF (25 mL), TEA (11.6 mL, 77.5 mmol) and Intermediate 13 (3 g, 16.4mmol) were added at rt and the mixture was stirred at 80° C. overnight.The reaction mixture was evaporated under vacuum and the resulting crudemixture was dissolved in EtOAc (100 mL), washed with water (20 mL),dried over anhydrous Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography to afford the title compound (yellowsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.13 (d, J=2.4 Hz, 1H), 7.64 (dd,J=9.2, 2.4 Hz, 1H), 7.15-7.11 (m, 1H), 6.78-6.71 (m, 3H), 4.52-4.48 (m,3H), 3.43-3.41 (m, 4H), 3.17-3.11 (m, 2H), 2.46-2.43 (m, 2H), 2.38-2.32(m, 2H), 1.28-1.25 (m, 3H). LCMS: (Method A) 388.0 (M+H), Rt. 2.34 min,90.08% (Max).

Step 2:1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-one

The title compound was synthesized according to the procedure describedfor Example 36, step 1, starting with1-(5-bromopyridin-2-yl)-4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazine(0.8 g, 2.00 mmol). The resulting crude product was purified by flashchromatography, affording the title compound. Yield: 53% (0.5 g, yellowsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.69 (s, 1H), 7.94 (d, J=9.2 Hz,1H), 7.15 (d, J=7.6 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 6.76 (d, J=7.2 Hz,1H), 6.72 (s, 1H), 4.53-4.48 (m, 3H), 3.65-3.64 (m, 4H), 3.16-3.11 (m,2H), 2.51-2.50 (m, 4H), 2.40 (s, 3H), 1.31 (d, J=9.20 Hz, 3H). LCMS:(Method A) 352.0 (M+H), Rt. 2.00 min, 98.60% (Max).

Step 3:1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-ol

The title compound was synthesized according to the procedure describedfor Example 36, step 2, starting with1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-one(0.1 g, 0.27 mmol) in dry MeOH (5 mL). The crude was purified by MDAutoprep HPLC (Method C) to get the title compound (off white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.02 (s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.14 (d,J=8.0 Hz, 1H), 6.76-6.71 (m, 3H), 4.99 (d, J=3.6 Hz, 1H), 4.52-4.47 (m,3H), 3.40-3.38 (m, 5H), 3.15-3.11 (m, 2H), 2.37-2.36 (m, 4H), 1.27 (dd,J=6.2, 2.8 Hz, 6H). LCMS: (Method B) 354.0 (M+H), Rt. 5.06 min, 97.55%(Max). HPLC: (Method A) Rt. 1.98 min, 98.32% (Max).

Example 48:2-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)propan-2-ol

The title compound was synthesized according to the procedure describedfor Example 85, starting from Example 62 (0.3 g, 0.39 mmol). The crudeproduct was purified by flash chromatography to get the title compound(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (s, 1H), 7.58 (d,J=8.8 Hz, 1H), 7.15 (d, J=6.8 Hz, 1H), 6.78-6.70 (m, 3H), 4.92 (s, 1H),4.51 (t, J=8.0 Hz, 2H), 3.39-3.34 (m, 5H), 3.14 (t, J=8.4 Hz, 2H),2.39-2.38 (m, 4H), 1.39 (s, 6H), 1.28 (d, J=5.60 Hz, 3H). LCMS: (MethodB) 368.0 (M+H), Rt. 5.28 min, 98.92% (Max). HPLC: (Method A) Rt. 2.07min, 98.89% (Max).

Example 49:1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-2-methylpropan-1-ol

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 4 and Intermediate 18 (palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.96 (s, 1H), 7.43 (dd,J=8.80, 2.00 Hz, 1H), 7.15 (d, J=7.60 Hz, 1H), 6.78-6.72 (m, 3H), 4.96(d, J=4.00 Hz, 1H), 4.51 (t, J=8.80 Hz, 2H), 4.10 (t, J=4.40 Hz, 1H),3.49-3.36 (m, 4H), 3.14 (t, J=8.80 Hz, 2H), 2.47-2.46 (m, 2H), 2.39-2.34(m, 2H), 1.79-1.74 (m, 1H), 1.28 (d, J=6.80 Hz, 3H), 0.87 (d, J=6.80 Hz,3H), 0.70 (d, J=6.80 Hz, 3H). LCMS: (Method A) 382.3 (M+H), Rt. 2.33min, 98.4% (Max). HPLC: (Method A) Rt 2.38 min, 99.4% (Max).

Example 50:1-(6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)-2,2,2-trifluoroethan-1-ol

The title compound was synthesized according to the procedure describedfor Example 87, starting from Example 62 (pale brown solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.13 (s, 1H), 7.57 (d, J=8.80 Hz, 1H), 7.14 (d, J=7.60Hz, 1H), 6.81-6.74 (m, 2H), 6.71-6.67 (m, 2H), 5.02 (s, 1H), 4.49 (t,J=8.80 Hz, 2H), 3.52-3.40 (m, 5H), 3.13 (t, J=8.40 Hz, 2H), 2.46-2.33(m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 408.0 (M+H), Rt. 2.73min, 94.3% (Max). HPLC: (Method A) Rt 2.67 min, 97.8% (Max).

Example 51: 2-(6-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyridin-3-yl) propan-2-ol

The title compound was synthesized according to the procedure describedfor Example 85, starting from Example 66 (off white solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.93 (d, J=5.2 Hz, 2H), 8.16 (s, 1H), 8.08 (d, J=8.8Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.57 (t, J=6.8 Hz, 1H),6.71 (d, J=9.2 Hz, 1H), 4.89 (d, J=6.0 Hz, 1H), 3.74 (d, J=6.8 Hz, 1H),3.42 (br s, 4H), 2.50 (br s, 4H), 1.43 (d, J=6.4 Hz, 3H), 1.37 (s, 6H).LCMS: (Method A) 378.3 (M+H), Rt. 1.651 min, 98.83% (Max). HPLC: (MethodA), Rt. 1.644 min, 98.54% (Max).

Example 52:1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-ol

The title compound was synthesized according to the procedure describedfor Example 84, starting from Intermediate 1 and Intermediate 16 (brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94-8.93 (m, 2H), 8.08 (d, J=8.8Hz, 1H), 8.01 (d, J=9.6 Hz, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.48 (d, J=8.4Hz, 1H), 6.74 (d, J=8.8 Hz, 1H), 4.99 (d, J=4.0 Hz, 1H), 4.62-4.59 (m,1H), 3.75-3.73 (m, 1H), 3.43-3.39 (m, 4H), 2.60-2.57 (m, 2H), 2.45-2.44(m, 2H), 1.43 (d, J=6.40 Hz, 3H), 1.28 (d, J=6.40 Hz, 3H). LCMS: (MethodB) 364.0 (M+H), Rt. 4.16 min, 98.12% (Max). HPLC: (Method A) Rt. 1.54min, 99.11% (Max).

Example 53:6-(1-(4-(6-methoxypyridin-3-yl)piperazin-1-yl)ethyl)quinoxaline

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 1 and1-(5-methoxy-2-pyridinyl)piperazine (brown solid). 1H NMR (400 MHz,DMSO-d₆): δ 8.93 (q, J=1.6 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s,1H), 7.91 (q, J=1.6 Hz, 1H), 7.74 (d, J=3.2 Hz, 1H), 7.40 (q, J=2.8 Hz,1H), 6.68 (d, J=8.8 Hz, 1H), 3.75 (s, 4H), 3.08-3.03 (m, 4H), 2.66-2.61(m, 4H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 350.0 (M+H), Rt.1.908 min, 97.686% (Max). HPLC: (Method A) Rt. 1.856 min, 98.999% (Max).

Example 54:5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-2(1H)-one

To a stirred solution of Example 53 (0.04 g, 0.114 mmol) in DCM (0.4 mL)cooled to 0° C. was added BBr₃ in DCM (1M) (0.24 mL, 0.228 mmol) and themixture was stirred at rt for 18 h. Reaction mixture was cooled to 0° C.and quenched with a saturated solution of NaHCO₃ (1 mL) and extractedwith DCM (2×10 mL), washed with brine (2 mL) and dried over Na₂SO₄. Theresulting crude product was purified by flash chromatography (eluent:10% MeOH in DCM), to afford the title product (dark fluffy solid). ¹HNMR (400 MHz, DMSO-d₆): δ 11.16 (s, 1H), 8.93 (d, J=6.8 Hz, 2H), 8.08(d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.89 (d, J=8.4 Hz, 1H), 7.38 (q, J=3.2Hz, 1H), 6.70 (s, 1H), 6.27 (d, J=9.6 Hz, 1H), 3.75-3.73 (m, 1H),2.88-2.81 (m, 4H), 2.62-2.56 (m, 4H), 1.42 (d, J=6.80 Hz, 3H). LCMS:(Method A) 336.2 (M+H), Rt. 1.555 min, 97.205% (Max). HPLC: (Method A)Rt. 1.523 min, 99.129% (Max).

Example 55:2-methyl-1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)propan-1-ol

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 1 and Intermediate 18 (palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (dd, J=7.20, 2.00 Hz,2H), 8.09 (d, J=8.40 Hz, 1H), 8.01 (d, J=1.20 Hz, 1H), 7.93 (d, J=2.00Hz, 1H), 7.91 (d, J=1.60 Hz, 1H), 7.43 (dd, J=8.80, 2.40 Hz, 1H), 6.75(d, J=8.80 Hz, 1H), 4.96 (d, J=4.40 Hz, 1H), 4.11-4.09 (m, 1H),3.76-3.74 (m, 1H), 3.52-3.38 (m, 4H), 2.59-2.57 (m, 2H), 2.48-2.45 (m,2H), 1.78-1.73 (m, 1H), 1.44 (d, J=6.80 Hz, 3H), 0.86 (d, J=6.80 Hz,3H), 0.69 (d, J=6.80 Hz, 3H). LCMS: (Method A) 392.3 (M+H), Rt. 1.93min, 99.2% (Max). HPLC: (Method A) Rt 1.97 min, 99.6% (Max).

Example 56:2,2,2-trifluoro-1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)ethan-1-ol

The title compound was synthesized according to the procedure describedfor Example 87, starting from Example 66 (pale brown solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.94-8.93 (m, 2H), 8.14 (s, 1H), 8.09 (d, J=8.40 Hz,1H), 8.01 (s, 1H), 7.93 (d, J=8.80 Hz, 1H), 7.58 (d, J=8.80 Hz, 1H),6.82 (d, J=8.80 Hz, 1H), 6.69 (d, J=5.60 Hz, 1H), 5.03 (t, J=6.40 Hz,1H), 3.77-3.75 (m, 1H), 3.54-3.45 (m, 4H), 2.60-2.59 (m, 4H), 1.44 (d,J=6.80 Hz, 3H). LCMS: (Method A) 418.2 (M+H), Rt. 2.12 min, 99.3% (Max).HPLC: (Method A) Rt 2.16 min, 99.3% (Max).

Example 57:4-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)tetrahydro-2H-pyran-4-ol

To a degassed solution of Intermediate 24 (125 mg, 0.58 mmol),Intermediate 2 (212 mg, 0.76 mmol) and sodium tert butoxide (432 mg,1.46 mmol) in 1,4 dioxane (4 mL) at rt, Pd₂(dba)₃ (27 mg, 0.03 mmol) andBINAP (36 mg, 0.05 mmol) were added. The reaction mixture was sealed andheated to 100° C. overnight. It was then filtered through celite andconcentrated. Water (4 mL) was added and was extracted with EtOAc (2×10mL). The combined organic layer was dried over Na₂SO₄ and concentrated.The crude product was purified by flash chromatography (eluent: 5-6%MeOH in DCM). After trituration in Et₂O and filtration, the titleproduct was isolated (brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93(d, J=5.2 Hz, 2H), 8.18 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H),7.91 (d, J=8.8 Hz, 1H), 7.62-7.50 (m, 1H), 6.74 (d, J=9.2 Hz, 1H), 4.92(s, 1H), 3.77-3.71 (m, 3H), 3.70-3.65 (m, 2H), 3.50-3.39 (m, 4H),2.63-2.52 (m, 4H), 1.91-1.87 (m, 2H), 1.53-1.50 (m, 2H), 1.43 (d, J=6.40Hz, 3H). LCMS: (Method A) 420.2 (M+H), Rt. 1.62 min, 95.40% (Max). HPLC:(Method A) Rt 1.59 min, 98.75% (Max).

Example 58:3-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)tetrahydrofuran-3-ol

The title compound was synthesized according to the procedure describedfor Example 57, starting from Intermediate 2 and Intermediate 25 (brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (dd, J=6.4, 2.6 Hz, 2H), 8.18(d, J=2.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.91 (d, J=8.4Hz, 1H), 7.56 (dd, J=8.8, 5.6 Hz, 1H), 6.75 (d, J=8.8 Hz, 1H), 3.98-3.92(m, 2H), 3.80-3.71 (m, 2H), 3.64 (d, J=8.8 Hz, 1H), 3.50-3.37 (m, 4H),2.59-2.55 (m, 2H), 2.47-2.39 (m, 3H), 2.19-2.13 (m, 1H), 2.08-2.04 (m,1H), 1.4 (d, J=6.8 Hz, 3H). LCMS: (Method A) 406.2 (M+H), Rt. 1.55 min,99.00% (Max). HPLC: (Method A) Rt 1.53 min, 99.39% (Max).

Example 59:3-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)oxetan-3-ol

The title compound was synthesized according to the procedure describedfor Example 57, starting from Intermediate 2 and Intermediate 26 (palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94-8.82 (m, 2H), 8.26 (d,J=2.4 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.4 Hz,1H), 7.68-7.65 (m, 1H), 6.81 (d, J=9.2 Hz, 1H), 6.22 (d, J=2.0 Hz, 1H),4.70-4.64 (m, 4H), 3.80-3.70 (m, 1H), 3.58-3.40 (m, 4H), 2.64-2.57 (m,2H), 2.49-2.43 (m, 2H), 1.43 (d, J=6.80 Hz, 3H). LCMS: (Method A) 392.2(M+H), Rt. 1.51 min, 98.29% (Max). HPLC: (Method A) Rt 1.49 min, 98.37%(Max).

Example 60:1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)cyclohexan-1-ol

The title compound was synthesized according to the procedure describedfor Example 57, starting from Intermediate 2 and Intermediate 27 (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (dd, J=7.2, 1.6 Hz, 2H),8.18 (d, J=2.4 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.93-7.91(m, 1H), 7.58 (d, J=2.4, 8.8 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 4.59 (s,1H), 3.76-3.74 (m, 1H), 3.48-3.43 (m, 4H), 2.60-2.56 (m, 2H), 2.46-2.43(m, 2H), 1.69-1.66 (m, 3H), 1.63-1.60 (m, 4H), 1.45-1.43 (m, 5H),1.30-1.20 (m, 1H). LCMS: (Method A) 418.2 (M+H), Rt. 2.18 min, 98.2%(Max). HPLC: (Method A) Rt 2.16 min, 98.9% (Max).

Example 61:1-(6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyridin-3-yl)cyclopentan-1-ol

The title compound was synthesized according to the procedure describedfor Example 57, starting from Intermediate 2 and Intermediate 30 (yellowsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (dd, J=1.6, 7.0 Hz, 2H), 8.18(d, J=2.0 Hz, 1H), 8.09 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.92 (dd,J=1.6, 8.4 Hz, 1H), 7.57 (dd, J=2.8, 8.8 Hz, 1H), 6.73 (d, J=8.8 Hz,1H), 4.68 (s, 1H), 3.76-3.74 (m, 1H), 3.45-3.44 (m, 4H), 2.61-2.58 (m,2H), 2.45-2.43 (m, 2H), 1.83-1.80 (m, 6H), 1.77-1.68 (m, 2H), 1.44 (d,J=6.40 Hz, 3H). LCMS: (Method A) 404.2 (M+H), Rt. 1.9 min, 98.6% (Max).HPLC: (Method A) Rt 1.8 min, 99.44% (Max).

Example 62: Methyl6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)nicotinate

The title compound was synthesized according to the procedure describedfor Example 66, replacing Intermediate 1 with Intermediate 4 (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (d, J=2.4 Hz, 1H), 7.91 (dd,J=9.2, 2.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.82 (d, J=9.2 Hz, 1H),6.76-6.71 (m, 2H), 4.49 (t, J=8.8 Hz, 2H), 3.77 (s, 3H), 3.62-3.61 (m,4H), 3.37-3.32 (m, 1H), 3.12 (t, J=8.8 Hz, 2H), 2.46-2.33 (m, 4H), 1.27(d, J=6.80 Hz, 3H). LCMS: (Method A) 368.3 (M+H), Rt. 2.83 min, 99.73%(Max). HPLC: (Method A) Rt 2.89 min, 99.60% (Max).

Example 63:6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylnicotinamide

To a stirred solution of Example 65 (250 mg, 0.7 mmol) in DMF (3 mL),HATU (322 mg, 0.84 mmol) was added at rt. The mixture was cooled to 0°C. and a solution of dimethylamine in THF (1.75 mL, 3.5 mmol, 2M) andDIPEA (271 mg, 2.1 mmol) were added. The resulting mixture was stirredat rt overnight. Completion of the reaction was monitored by TLC.Reaction mixture was evaporated. The resulting crude mixture wasdissolved in EtOAc (40 mL), washed with water (5 mL), a solution of 10%NaHCO₃ (5 mL), dried over Na₂SO₄ and evaporated. The crude product waspurified by flash chromatography (3-4% MeOH in DCM as eluent) andfurther purified by MD Autoprep HPLC (Method C) to afford the titleproduct (beige thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.20-8.17 (m,1H), 7.57 (dd, J=8.8, 2.4 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 6.78-6.71 (m,3H), 4.49 (t, J=8.8 Hz, 2H), 3.52-3.51 (m, 4H), 3.16-3.10 (m, 3H), 2.95(s, 6H), 2.39-2.32 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A)381.2 (M+H), Rt. 2.24 min, 97.05% (Max). HPLC: (Method A) Rt. 2.28 min,99.83% (Max).

Example 64:6-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methylnicotinamide

Example 64 was synthesized according to the protocol followed forExample 63, replacing the dimethylamine with a methylamine solution inTHF (1.75 mL, 3.5 mmol, 2M). The crude product was purified by flashchromatography (2% MeOH in DCM as eluent) to afford the title product(pale brown solid). ¹H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=2.4 Hz, 1H),8.17 (d, J=4.4 Hz, 1H), 7.89 (dd, J=9.0, 2.0 Hz, 1H), 7.14 (d, J=7.6 Hz,1H), 6.79-6.71 (m, 3H), 4.50 (t, J=8.4 Hz, 2H), 3.55-3.35 (m, 4H), 3.13(t, J=8.8 Hz, 2H), 2.73 (d, J=4.4 Hz, 3H), 2.55-2.34 (m, 4H), 1.28 (d,J=6.40 Hz, 3H). LCMS: (Method A) 367.3 (M+H), Rt. 2.14 min, 98.04%(Max). HPLC: (Method A) Rt. 2.16 min, 96.78% (Max).

Example 65:6-(4-(1-(2,3-Dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)nicotinic acid

To a stirred solution of Example 62 (750 mg, 2.0 mmol) in THF:H₂Omixture (9:1, 5 mL), LiOH (128 mg, 3.06 mmol) was added at rt and theresulting mixture was heated to 55° C. overnight. Completion of thereaction was monitored by TLC. Reaction mixture was neutralized withcitric acid and evaporated at 45° C. under reduced pressure. The residuewas dissolved in 10% MeOH in DCM (50 mL), filtrated and evaporated underreduced pressure. The resulting crude product was purified by MDAutoprep HPLC (Method B) to afford the title product. Yield: 83% (600mg, pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.50 (s, 1H), 7.86(d, J=8.4 Hz, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.77-6.71 (m, 2H), 6.60 (d,J=8.4 Hz, 1H), 4.49 (t, J=8.4 Hz, 2H), 3.43-3.37 (m, 4H), 3.32-3.31 (m,1H), 3.13 (t, J=8.4 Hz, 2H), 2.45-2.33 (m, 4H), 1.27 (d, J=6.80 Hz, 3H).LCMS: (Method A) 354.2 (M+H), Rt. 2.30 min, 99.16% (Max). HPLC: (MethodA) Rt. 2.33 min, 99.61% (Max).

Example 66: Methyl-6-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)nicotinate

To a stirred solution of Intermediate 9 (5.35 g, 20.76 mmol) in dry DMF(55 mL), TEA (14.46 mL, 103.81 mmol) and Intermediate 1 (4 g, 20.76mmol) were added. The reaction mixture was stirred at 80° C. overnight.Resulting reaction mixture was cooled to rt and solvent was evaporatedunder vacuum. The crude product was dissolved in EtOAc (200 mL) andwashed with water (40 mL). The organic layer was dried over anhydrousNa₂SO₄ and concentrated. The product was purified by flashchromatography to afford the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.94 (dd, J=6.8, 1.6 Hz, 2H), 8.62 (s, 1H), 8.10(d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.92 (d, J=11.6 Hz, 2H), 6.84 (d, J=8.8Hz, 1H), 3.79 (br s, 1H), 3.78 (s, 3H), 3.65 (br s, 4H), 2.61-2.56 (m,2H), 2.51-2.43 (m, 2H), 1.45 (d, J=6.40 Hz, 3H). LCMS: (Method A) 378.3(M+H), Rt. 2.24 min, 99.68% (Max). HPLC: (Method A), Rt. 2.30 min,99.34% (Max).

Example 67: 6-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl) nicotinicacid

To a stirred solution of Example 66 (1.2 g, 3.179 mmol) in THF (12 mL),MeOH (6 mL) and water (2 mL), LiOH—H₂O (0.2 g, 4.768 mmol) was added atrt and the resulting mixture was stirred for 14 h at same temperature.The reaction mixture was evaporated under vacuum and the resulting crudemixture was acidified to pH=4 with 1.5 N HCl solution. It was extractedwith 10% methanol in DCM (30 mL). The organic layer was dried overanhydrous Na₂SO₄ and concentrated. The resulting crude product waspurified by flash chromatography to give title compound. Yield: 51% (600mg, off white solid). ¹H NMR (400 MHz, MEOD): δ 8.98 (s, 2H), 8.75 (d,J=2.0 Hz, 1H), 8.31-8.27 (m, 2H), 8.11 (dd, J=9.0, 2.4 Hz, 1H), 8.02(dd, J=2.0, 9.0 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 4.80 (q, J=6.8 Hz, 1H),4.57-0.00 (m, 8H), 1.94 (d, J=6.8 Hz, 3H). LCMS: (Method A) 364.2 (M+H),Rt. 1.74 min, 99.73% (Max). HPLC: (Method A), Rt. 1.75 min, 99.87%(Max).

Example 68: N-methyl-6-(4-(1-(quinoxalin-6-yl)ethyl piperazin-1-yl)picolinamide

A stirred solution of Intermediate 2 (0.6 g, 1.91 mmol) in dry1,4-dioxane (10 mL), was added cesium carbonate (1.9 g, 5.88 mmol)followed by 6-chloro-N-methylpicolinamide (0.25 g, 1.47 mmol, ABCR).Nitrogen was flushed into the solution for 20 min and Pd(OAc)₂ (0.016 g,0.07 mmol) and 2-2′-bis (diphenylphosphino)-1-1′-binaphthyl (0.091 g,0.14 mmol) were added. The reaction mixture was stirred at 100° C. for12 h. The resulting reaction mixture was filtered through celite andevaporated under vacuum. Water (5 mL) was added and the mixture wasextracted with EtOAc (50 mL). The organic layer was dried over anhydrousNa₂SO₄ and evaporated. The resulting crude product was purified bycolumn chromatography (brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.94-8.92 (m, 2H), 8.41 (d, J=4.0 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 8.01(s, 1H), 7.94-7.94 (m, 1H), 7.63 (t, J=8.4 Hz, 1H), 7.25-7.23 (m, 1H),6.94 (d, J=8.4 Hz, 1H), 3.79-3.77 (m, 1H), 3.58-3.58 (m, 4H), 2.77 (d,J=4.80 Hz, 3H), 2.59-2.58 (m, 2H), 2.49-2.45 (m, 2H), 1.45 (d, J=6.80Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 2.14 min, 95.23% (Max). HPLC:(Method A) Rt. 2.07 min, 96.75% (Max).

Example 69: N, N-dimethyl-6-(4-(1-(quinoxalin-6-yl) ethyl)piperazin-1-yl) picolinamide

The title compound was synthesized according to the procedure describedfor Example 68, starting from Intermediate 2 and6-chloro-N,N-dimethylpicolinamide. The resulting crude product waspurified by MD Autoprep HPLC (Method C). (yellow solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.94 (d, J=5.2 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01(s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 6.84 (d, J=8.4Hz, 1H), 6.75 (d, J=7.2 Hz, 1H), 3.78-3.76 (m, 1H), 3.50-3.49 (m, 4H),2.95-2.92 (m, 6H), 2.60 (t, J=5.20 Hz, 2H), 2.46-2.45 (m, 2H), 1.45 (d,J=6.40 Hz, 3H), LCMS: (Method A) 391.2 (M+H), Rt. 99.57 min, 98.20%(Max). HPLC: (Method A) Rt. 2.06 min, 99.57% (Max).

Example 70: Methyl6-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)picolinate

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 2 and methyl6-chloropicolinate The crude product was purified by flashchromatography (Eluent: 2.3% MeOH in DCM), to afford the title compound(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (d, J=5.2 Hz, 2H),8.10 (d, J=8.4 Hz, 1H), 8.02 (s, 1H), 7.93 (d, 8.2 Hz, 1H), 7.66 (t,J=8.4 Hz, 1H), 7.29 (d, J=7.2 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.81-3.75(m, 4H), 3.60-3.40 (m, 4H), 2.68-2.51 (m, 2H), 2.39-2.33 (m, 2H), 1.45(d, J=6.80 Hz, 3H). LCMS: (Method A) 378.2 (M+H), Rt. 2.46 min, 97.78%(Max). HPLC: (Method A) Rt. 2.38 min, 97.32% (Max).

Example 71:1-(5-(methylsulfonyl)pyridin-2-yl)-4-(1-(2,3,3a,7a-tetrahydrobenzofuran-6-yl)ethyl)piperazine

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 13 and2-chloro-5-(methylsulfonyl)-pyridine (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.47 (d, J=2.4 Hz, 1H), 7.86 (dd, J=9.2, 2.4 Hz, 1H), 7.15(d, J=7.6 Hz, 1H), 6.91 (d, J=9.2 Hz, 1H), 6.77-6.72 (m, 2H), 4.51 (t,J=8.8 Hz, 2H), 3.64 (t, J=4.8 Hz, 4H), 3.38 (d, J=6.8 Hz, 1H), 3.18-3.11(m, 5H), 2.47-2.35 (m, 4H), 1.29 (d, J=6.80 Hz, 3H). LCMS: (Method A)388.0 (M+H), Rt. 2.63 min, 97.77% (Max). HPLC: (Method A) Rt 2.61 min,99.72% (Max).

Example 72:6-(1-(4-(5-(methylsulfonyl)pyridin-2-yl)piperazin-1-yl)ethyl)quinoxaline

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 2 and2-chloro-5-(methylsulfonyl)-pyridine (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.93 (dd, J=6.8, 1.6 Hz, 2H), 8.46 (d, J=2.8 Hz, 1H), 8.09(d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.91 (dd, J=8.6, 2.0 Hz, 1H), 7.85 (dd,J=9.2, 2.8 Hz, 1H), 3.78 (d, J=6.8 Hz, 1H), 3.67 (s, 4H), 3.13 (s, 3H),2.67-2.55 (m, 2H), 2.46-2.32 (m, 2H), 1.44 (d, J=6.40 Hz, 3H). LCMS:(Method A) 398.0 (M+H), Rt. 2.04 min, 98.07% (Max). HPLC: (Method A) Rt2.01 min, 99.13% (Max).

Example 73:(2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)methanol

The title compound was synthesized according to the procedure describedfor Examples 98 and 75, starting from Intermediate 3 and Intermediate 12(brown thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 9.37 (s, 1H), 8.26 (s,2H), 8.11 (d, J=8.40 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J=8.40 Hz, 1H),5.03 (t, J=5.20 Hz, 1H), 4.29 (d, J=5.60 Hz, 2H), 3.71-3.68 (m, 4H),3.66-3.63 (m, 1H), 2.46-2.38 (m, 4H), 1.39 (d, J=6.40 Hz, 3H). LCMS:(Method A) 356.3 (M+1), Rt. 1.97 min, 97.5% (Max). HPLC: (Method A) Rt2.07 min, 98.2% (Max).

Example 74: 2-(2-(4-(1-(2, 3-dihydrobenzofuran-6-yl) ethyl)piperazin-1-yl) pyrimidin-5-yl) propan-2-ol

The title compound was synthesized according to the procedure describedfor Example 85, starting from Example 98 (0.2 g, 0.54 mmol). The crudeproduct was purified by flash chromatography to get the title compound(pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (s, 2H), 7.13 (d,J=7.2 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.70 (s, 1H), 5.04 (s, 1H), 4.49(t, J=8.8 Hz, 2H), 3.64-3.63 (m, 5H), 3.12 (t, J=8.8 Hz, 2H), 2.44-2.42(m, 4H), 1.38 (s, 6H), 1.25 (d, J=6.4 Hz, 3H). LCMS: (Method A) 369.2(M+H), Rt. 2.52 min, 98.68% (Max). HPLC: (Method A) Rt. 2.59 min, 99.01%(Max).

Example 75: (2-(4-(1-(2,3-Dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl) methanol

To a stirred solution of Example 98 (0.1 g, 0.27 mmol) in dry THF (4 mL)cooled at −10° C., lithium aluminium hydride (0.17 mL, 0.35 mmol, 2M inTHF, Symax Fine Chemicals) was added drop wise and the reaction mixturewas stirred at same temperature for 10 min. The resulting reactionmixture was quenched with a saturated solution of NH₄Cl (3 mL) andextracted with EtOAc (20 mL). The organic layer was washed with brine (4mL), dried over anhydrous Na₂SO₄ and concentrated. The resulting crudeproduct was purified by flash chromatography (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.26 (s, 2H), 7.13 (d, J=7.6 Hz, 1H), 6.73 (d,J=7.2 Hz, 1H), 6.70 (s, 1H), 5.02 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 4.27(d, J=5.2 Hz, 2H), 3.66 (t, J=4.4 Hz, 4H), 3.12 (t, J=8.8 Hz, 2H),2.44-2.43 (m, 4H), 1.26 (d, J=6.4 Hz, 3H).LCMS: (Method A) 341.1 (M+H),Rt. 2.22 min, 99.42% (Max). HPLC: (Method A) Rt. 2.24 min, 99.45% (Max).

Example 76:1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclopropan-1-ol

To a stirred solution of Example 98 (200 mg, 0.5 mmol) in THF (3 mL),titanium iso propoxide (78 mg, 0.27 mmol) was added. Then ethylmagnesium bromide in diethyl ether (0.54 mL, 1.6 mmol, 3M) was addedslowly at 20° C. for 1 h and the mixture was stirred 3 h at the sametemperature. Completion of the reaction was monitored by TLC. Thereaction mixture was quenched with saturated ammonium chloride solution(10 mL), the product was extracted with EtOAc (2×20 mL). Combinedorganic layer was dried over Na₂SO₄ and concentrated. The resultingcrude product was purified by flash chromatography (Eluant: 3-5% MeOH inDCM) and further purified by preparative HPLC (Method B) to afford thetitle product (pale yellow solid).

¹H NMR (400 MHz, DMSO-d6): δ 8.24 (s, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.76(dd, J=7.6, 1.2 Hz, 1H), 6.72 (s, 1H), 5.91 (s, 1H), 4.50 (t, J=8.8 Hz,2H), 3.67-3.65 (m, 4H), 3.35-3.34 (m, 1H), 3.13 (t, J=8.8 Hz, 2H),2.45-2.32 (m, 4H), 1.28 (d, J=6.4 Hz, 3H), 0.99-0.96 (m, 2H), 0.87-0.84(m, 2H). LCMS: (Method A) 367.3 (M+H), Rt. 2.55 min, 99.03% (Max). HPLC:(Method A) Rt 2.60 min, 98.90% (Max).

Example 77:1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-2,2,2-trifluoroethan-1-ol

The title compound was synthesized according to the procedure describedfor Example 87, starting from Example 75 (pale green solid). ¹H NMR (400MHz, DMSO-d6): δ 8.37 (s, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.84 (d, J=5.6Hz, 1H), 6.76-6.71 (m, 2H), 5.07 (t, J=6.8 Hz, 1H), 4.50 (t, J=8.8 Hz,2H), 3.71-3.69 (m, 4H), 3.37-3.31 (m, 1H), 3.13 (t, J=8.8 Hz, 2H),2.44-2.32 (m, 4H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 409.2(M+H), Rt. 3.04 min, 97.18% (Max). HPLC: (Method A) Rt 3.15 min, 99.10%(Max).

Example 78:1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-2-methylpropan-1-ol

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 4 and Intermediate 20 (paleyellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.22 (s, 2H), 7.14 (d, J=7.6Hz, 1H), 6.76-6.71 (m, 2H), 5.08 (d, J=4.4 Hz, 1H), 4.49 (t, J=8.4 Hz,2H), 4.12-4.09 (m, 1H), 3.67-3.65 (m, 4H), 3.32-3.31 (m, 1H), 3.12 (t,J=8.8 Hz, 2H), 2.45-2.32 (m, 4H), 1.80-1.78 (m, 1H), 1.27 (d, J=6.40 Hz,3H), 0.85 (d, J=6.40 Hz, 3H), 0.71 (d, J=6.40 Hz, 3H). LCMS: (Method A)383.3 (M+H), Rt. 2.93 min, 99.74% (Max). HPLC: (Method A) Rt 3.01 min,99.32% (Max).

Example 79:3-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydrofuran-3-ol

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 13 and Intermediate 28 (brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (s, 2H), 7.14 (d, J=7.6 Hz,1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 5.39 (s, 1H), 4.49 (t, J=8.8Hz, 2H), 3.95-3.94 (m, 2H), 3.77-3.75 (m, 1H), 3.68-3.67 (m, 4H),3.16-3.15 (m, 2H), 2.44-2.43 (m, 2H), 2.34-2.33 (m, 2H), 2.21-2.01 (m,4H), 1.27 (d, J=6.80 Hz, 2H). LCMS: (Method A) 397.2 (M+H), Rt. 2.331min, 97.394% (Max). HPLC: (Method A) Rt. 2.375 min, 96.579% (Max).

Example 80:1-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)cyclohexan-1-ol

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 13 and Intermediate 22 (brownthick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (s, 2H), 7.15 (d, J=7.6Hz, 1H), 6.76 (d, J=7.2 Hz, 1H), 6.72 (s, 1H), 4.74 (s, 1H), 4.50 (t,J=8.8 Hz, 2H), 3.66 (t, J=4.8 Hz, 4H), 3.34 (s, 1H), 3.13 (t, J=8.8 Hz,2H), 2.44-2.43 (m, 2H), 2.34 (q, J=4.80 Hz, 2H), 1.67-1.64 (m, 7H),1.46-1.43 (m, 2H), 1.28 (d, J=6.40 Hz, 3H). LCMS: (Method A) 409.2(M+H), Rt. 3.185 min, 99.358% (Max). HPLC: (Method A) Rt. 3.253 min,99.334% (Max).

Example 81:4-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 13 and Intermediate 23. Thecrude product was purified by MD Autoprep HPLC (Method B) to get thetitle compound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (d,J=6.4 Hz, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.76-6.71 (m, 2H), 5.06 (s, 1H),4.49 (t, J=8.8 Hz, 2H), 3.74-3.65 (m, 8H), 3.34-3.31 (m, 1H), 3.12 (t,J=8.8 Hz, 2H), 2.43-2.39 (m, 2H), 2.34-2.31 (m, 2H), 1.90-1.89 (m, 2H),1.56-1.53 (m, 2H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 411.2(M+H), Rt. 2.38 min, 98.92% (Max). HPLC: (Method A) Rt. 2.43 min, 98.50%(Max).

Example 82:3-(2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)oxetan-3-ol

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 13 and Intermediate 34. Theresulting crude product was purified by column chromatography (eluent:3% MeOH in DCM) to afford the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 8.49 (s, 2H), 7.15 (d, J=7.6 Hz, 1H), 6.76 (d,J=7.6 Hz, 1H), 6.72 (s, 1H), 6.35 (s, 1H), 4.70 (s, 4H), 4.50 (t, J=8.8Hz, 2H), 3.70 (t, J=4.8 Hz, 4H), 3.36-0.00 (m, 1H), 3.13 (t, J=8.4 Hz,2H), 2.45-2.44 (m, 2H), 2.37-2.36 (m, 2H), 1.28 (d, J=6.80 Hz, 3H).LCMS: (Method A) 383.3 (M+H), Rt. 2.317 min, 98.76% (Max). HPLC: (MethodA) Rt. 2.334 min, 99.04% (Max).

Example 83:1-(2-(4-(1-(1,8-naphthyridin-2-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)-2,2,2-trifluoroethan-1-ol

The title compound was synthesized according to the procedure describedfor Example 87, starting from Intermediate 29 (pale brown solid). ¹H NMR(400 MHz, DMSO-d₆): δ 9.05-9.04 (m, 1H), 8.44 (d, J=8.8 Hz, 2H), 8.38(s, 2H), 7.80 (d, J=8.4 Hz, 1H), 7.62-7.59 (m, 1H), 6.84 (d, J=6.0 Hz,1H), 5.09-5.06 (m, 1H), 3.89-3.87 (m, 1H), 3.75-3.74 (m, 4H), 2.67-2.57(m, 2H), 2.50-2.32 (m, 2H), 1.43 (d, J=6.80 Hz, 3H). LCMS: (Method A)419.2 (M+H), Rt. 2.25 min, 96.08% (Max). HPLC: (Method A) Rt 2.27 min,97.02% (Max).

Example 84: 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyrimidin-5-yl) ethan-1-ol

Step 1: 6-(1-(4-(5-bromopyrimidin-2-yl) piperazin-1-yl) ethyl)quinoxaline

To a stirred solution of Intermediate 14 (2.5 g, 8.99 mmol) in dry DMF(25 mL), TEA (4.9 mL, 35.9 mmol) and Intermediate 1 (2.6 g, 13.4 mmol)were added at rt. The resulting mixture was heated at 80° C. overnight.It was concentrated under vacuum and the resulting crude mixture wasdissolved in EtOAc (100 mL), washed with water (20 mL), dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified byflash chromatography, affording the title compound (yellow solid). ¹HNMR (400 MHz, DMSO-d₆): δ 8.92 (d, J=5.6 Hz, 2H), 8.30 (s, 2H), 8.19 (d,J=8.4 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.4 Hz, 1H), 3.69-3.67 (m, 5H),2.77-2.75 (m, 4H), 1.42 (d, J=6.8 Hz, 3H). LCMS: (Method A) 401.2 (M+H),Rt. 2.60 min, 70.09% (Max).

Step 2: 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyrimidin-5-yl) ethan-1-one

The title compound was synthesized according to the procedure describedfor Example 36, step 1, starting with 6-(1-(4-(5-bromopyrimidin-2-yl)piperazin-1-yl) ethyl) quinoxaline (0.8 g, 2.00 mmol). The resultingcrude product was purified by flash chromatography, affording the titlecompound (yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (d, J=5.2 Hz,2H), 8.83 (s, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.92 (d, J=8.8Hz, 1H), 3.88-3.86 (m, 5H), 2.57-2.56 (m, 2H), 2.50-2.49 (m, 5H), 1.44(d, J=6.8 Hz, 3H). LCMS: (Method A) 363.3 (M+H), Rt. 2.02 min, 90.62%(Max).

Step 3: 1-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyrimidin-5-yl) ethan-1-ol

The title compound was synthesized according to the procedure describedfor Example 36, step 2, starting with 1-(2-(4-(1-(quinoxalin-6-yl)ethyl) piperazin-1-yl) pyrimidin-5-yl) ethan-1-one (0.1 g, 0.27 mmol) indry THF: MeOH (1:1, 5 mL). The crude was purified by flashchromatography to give the title product. Yield: 67% (0.067 g, off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (dd, J=5.6 Hz, 2H), 8.28 (s,2H), 8.08 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 5.05(d, J=4.4 Hz, 1H), 4.61-4.58 (m, 1H), 3.74-3.69 (m, 5H), 2.59-2.57 (m,2H), 2.42-2.40 (m, 2H), 1.42 (d, J=6.8 Hz, 3H), 1.39 (d, J=6.4 Hz, 3H).LCMS: (Method A) 365.2 (M+H), Rt. 1.87 min, 99.74% (Max). HPLC: (MethodA) Rt. 1.89 min, 99.44% (Max).

Example 85: 2-(2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyrimidin-5-yl) propen-2-ol

To a stirred solution of Example 105 (0.15 g, 0.39 mmol) in dry THF (5mL), methyl magnesium chloride (0.4 mL, 1.19 mmol, 3M in THF, Symax FineChemicals) was added drop wise at −40° C. and the resulting mixture wasstirred at rt for 2 h. It was quenched with a saturated solution ofNH₄Cl (3 mL) and was extracted with EtOAc (20 mL). The organic phase waswashed with brine (5 mL), dried over anhydrous Na₂SO₄ and concentrated.The resulting crude product was purified by flash chromatographyfollowed by MD Autoprep HPLC (Method C), affording the title compound(off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93-8.91 (m, 2H), 8.38(s, 2H), 8.08 (d, J=8.8 Hz, 1H), 7.99 (s, 1H), 7.90 (d, J=8.8 Hz, 1H),5.04 (s, 1H), 3.74-3.72 (m, 5H), 2.55-2.53 (m, 2H), 2.41-2.40 (m, 2H),1.42 (d, J=6.8 Hz, 3H), 1.38 (s, 6H). LCMS: (Method A) 379.0 (M+H), Rt.2.10 min, 99.26% (Max). HPLC: (Method A) Rt. 2.04 min, 99.15% (Max).

Example 86:(2-(4-(1-(Quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl) methanol

The title product was prepared according to the protocol described forExample 75, starting from Example 105. The resulting crude product waspurified by flash chromatography (brown thick oil). ¹H NMR (400 MHz,DMSO-d₆): δ 8.92 (d, J=5.6 Hz, 2H), 8.76 (s, 2H), 8.08 (d, J=12.0 Hz,1H), 7.99 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 5.04 (t, J=5.6 Hz, 1H), 4.27(d, J=5.2 Hz, 2H), 3.73 (t, J=6.8 Hz, 5H), 2.40 (t, J=5.2 Hz, 4H), 1.42(d, J=6.4 Hz, 3H). LCMS: (Method A) 351.2 (M+H), Rt. 1.689 min, 97.79%(Max). HPLC: (Method A) Rt. 1.72 min, 99.19% (Max).

Example 87: 2, 2, 2-trifluoro-1-(2-(4-(1-(quinoxalin-6-yl) ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

Step 1: 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyrimidine-5-carbaldehyde

A stirred solution of Example 86 (0.65 g, 1.85 mmol) in dry DCM (110mL), Desmartin periodinane (1.58 g, 3.71 mmol) was added at 0° C. andthe mixture was stirred for 1 h at the same temperature. The reactionmixture was diluted with DCM (30 mL) and washed with a saturatedsolution of NaHCO₃ (2×5 mL). The resulting DCM layer was dried overanhydrous Na₂SO₄ and evaporated under vacuum. The crude product waspurified by flash chromatography, affording the title compound. Yield:50% (0.33 g, yellow thick oil). ¹H NMR (400 MHz, DMSO-d6: δ 9.79 (s,1H), 8.94 (d, J=4.8 Hz, 2H), 8.84 (s, 1H), 8.77-8.77 (m, 2H), 8.12-8.09(m, 2H), 4.23-4.18 (m, 5H), 3.97-3.91 (m, 4H), 1.45 (d, J=19.6 Hz, 3H).LCMS: (Method A) 349.0 (M+2), Rt. 1.98 min, 64.53% (Max).

Step 2: 2, 2, 2-trifluoro-1-(2-(4-(1-(quinoxalin-6-yl) ethyl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-ol

A stirred solution of 2-(4-(1-(quinoxalin-6-yl) ethyl) piperazin-1-yl)pyrimidine-5-carbaldehyde (0.15 g, 0.43 mmol) in dry DMF (2 mL), K₂CO₃(0.118 g, 0.86 mmol) and (trifluoromethyl) trimethylsilane (0.122 g,0.86 mmol) were added at 10° C. and the mixture was stirred at rt for 1h. It was quenched with water (2 mL) and extracted with EtOAc (15 mL).The EtOAc layer was dried over anhydrous Na₂SO₄ and evaporated undervacuum. The resulting crude was purified by flash chromatographyfollowed by MD Autoprep HPLC (Method C) (off white solid). ¹H NMR (400MHz, DMSO-d6): δ 8.93 (dd, J=1.6, 2H), 8.39 (s, 2H), 8.09 (d, J=8.8 Hz,1H), 8.01 (d, J=1.6 Hz, 1H), 7.94-7.94 (m, 1H), 6.83 (d, J=6.0 Hz, 1H),5.09 (t, J=6.8 Hz, 1H), 3.78-3.77 (m, 5H), 2.52-2.51 (m, 2H), 2.50-2.50(m, 2H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 419.2 (M+2), Rt. 2.46min, 99.11% (Max). HPLC: (Method A) Rt. 2.53 min, 99.48% (Max).

Example 88: 2-methyl-1-(2-(4-(1-(quinoxalin-6-yl)ethyl) piperazin-1-yl)pyrimidin-5-yl) propan-1-ol

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 1 and Intermediate 20 (offwhite solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (dd, J=7.2, 1.6 Hz, 2H),8.23 (s, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93 (dd, J=8.8, 1.6Hz, 1H), 5.09 (d, J=4.4 Hz, 1H), 4.13-4.12 (m, 1H), 3.77-3.75 (m, 1H),3.71 (t, J=4.4 Hz, 4H), 2.44-2.43 (m, 4H), 1.80-1.79 (m, 1H), 1.44 (d,J=6.80 Hz, 3H), 0.86 (d, J=6.80 Hz, 3H), 0.72 (d, J=6.80 Hz, 3H). LCMS:(Method A) 393.2 (M+H), Rt. 2.37 min, 96.65% (Max). HPLC: (Method A) Rt.2.43 min, 99.62% (Max).

Example 89:4-(2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)tetrahydro-2H-pyran-4-ol

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 2 and Intermediate 23 (44 mg,pale brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93-8.92 (m, 2H), 8.41(s, 2H), 8.08 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 7.91 (d, J=8.4 Hz, 1H),5.06 (s, 1H), 3.76-3.66 (m, 9H), 2.42-2.40 (m, 4H), 1.92-1.89 (m, 2H),1.55-1.52 (m, 2H), 1.43 (d, J=6.00 Hz, 3H). LCMS: (Method A) 421.2(M+2H), Rt. 1.96 min, 98.37% (Max). HPLC: (Method A) Rt. 1.92 min,99.41% (Max).

Example 90: 2-(4-(1-(2, 3-dihydrobenzofuran-6-yl) ethyl)piperazin-1-yl)-5-methylpyrimidine

To a stirred solution of Example 98 (0.3 g, 0.82 mmol) in dry THF (6mL), lithium aluminium hydride solution (0.17 mL, 0.35 mmol, 2M in THF,Symax Fine Chemicals) was added drop wise at 0° C. and the resultingmixture was stirred at rt for 1 h. It was quenched with a saturatedsolution of NH₄Cl (10 mL) and extracted with EtOAc (35 mL). The organiclayer was washed with brine, dried over anhydrous Na₂SO₄ andconcentrated. The resulting crude product was purified by flashchromatography, affording the title compound (off white solid). ¹H NMR(400 MHz, DMSO-d₆): 8.19 (s, 2H), 7.14 (d, J=7.6 Hz, 1H), 6.75 (d, J=8.4Hz, 1H), 6.71 (s, 1H), 4.49 (t, J=8.4 Hz, 2H), 3.63-3.61 (m, 5H), 3.12(t, J=8.8 Hz, 2H), 2.51-2.49 (m, 2H), 2.40-2.39 (m, 2H), 2.05 (s, 3H),1.26 (d, J=6.4 Hz, 3H). LCMS: (Method A) 325.2 (M+H), Rt. 2.75 min,98.02% (Max). HPLC: (Method A) Rt. 2.77 min, 98.513% (Max).

Example 91:7-(1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)imidazo[1,2-a]pyridine

To a stirred solution of 2-chloro-5-(trifluoromethyl)pyrimidine (0.15 g,0.83 mmol) in dry DMF (7 mL), TEA (0.43 mL, 3.12 mmol) and Intermediate8 (0.24 g, 1.04 mmol) were added at 0° C. The reaction mixture wasstirred at 100° C. for 12 h. The reaction mixture was concentrated undervacuum to give a crude product, which was purified by flash columnchromatography using 2-3% MeOH in DCM as eluent. The title compound wasisolated after evaporation of the solvents (dark brown thick oil). ¹HNMR (400 MHz, DMSO-d₆): δ 8.66 (s, 2H), 8.48 (d, J=7.2 Hz, 1H), 7.88 (s,1H), 7.52 (s, 1H), 7.43 (s, 1H), 6.93 (d, J=6.8 Hz, 1H), 3.82 (t, J=4.4Hz, 4H), 3.60-3.50 (m, 1H), 2.59-2.51 (m, 2H), 2.49-2.38 (m, 2H), 1.34(d, J=6.8 Hz, 3H). LCMS: (Method A) 377.2 (M+H), Rt. 2.29 min, 99.4%(Max). HPLC: (Method A) Rt 2.33 min, 99.18% (Max).

Example 92:2-(1-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)ethyl)-1,8-naphthyridine

The title compound was synthesized according to the procedure describedfor Example 12, using Intermediate 29 and2-(1-piperazinyl)-5-(trifluoromethyl)-pyrimidine (brown thick oil). ¹HNMR (400 MHz, DMSO-d₆): δ 9.06-9.04 (m, 1H), 8.67 (s, 2H), 8.46 (d,J=8.4 Hz, 2H), 7.81 (d, J=8.4 Hz, 1H), 7.63-7.60 (m, 1H), 3.92-3.90 (m,1H), 3.85-3.84 (m, 4H), 2.64-2.60 (m, 2H), 2.47-2.43 (m, 2H), 1.45 (d,J=6.8 Hz, 3H). LCMS: (Method A) 389.2 (M+H), Rt. 2.72 min, 98.07% (Max).HPLC: (Method A) Rt. 2.76 min, 98.46% (Max).

Example 94:6-(1-(4-(5-(cyclopent-1-en-1-yl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

Step 1: tert-butyl4-(5-(1-hydroxycyclopentyl)pyrimidin-2-yl)piperazine-1-carboxylate

A solution of the tert-butyl4-(5-bromopyrimidin-2-yl)piperazine-1-carboxylate (1.5 g, 4.37 mmol) indry diethyl ether was cooled to −80° C. and kept under inert atmosphere.n-BuLi (1.6 mL, 5.24 mmol, 2.5 m in Hexane) was added dropwise. Thesolution was allowed stand at −80° C. for 1 h and cyclopentanone (1.2equiv) was added slowly to reaction mixture at same temperature. After15 min, the temperature was increased to rt and the mixture was stirredfor 1 h at rt. It was quenched with a saturated solution of NH₄Cl (3 mL)and extracted with EtOAc (3×50 mL). The organic phase was washed withbrine (5 mL), dried over anhydrous Na₂SO₄ and concentrated. The crudeproduct was purified by flash chromatography to afford the titlecompound. ¹H NMR 400 MHz, DMSO-d₆: δ 8.48 (s, 2H), 3.83 (t, J=5.2 Hz,4H), 3.52 (t, J=5.2 Hz, 4H), 2.02-1.94 (m, 6H), 1.85-1.84 (m, 2H). LCMS:(Method A) 349.0 (M+H), Rt. 2.39 min, 98.13% (Max).

Step 2: 5-(cyclopent-1-en-1-yl)-2-(piperazin-1-yl)pyrimidinehydrochloride

To a stirred solution of tert-butyl4-(5-(1-hydroxycyclopentyl)pyrimidin-2-yl)piperazine-1-carboxylate (250mg, 0.71 mmol) in 1,4-dioxane (5 mL), HCl in 1,4-dioxane (2.5 mL, 4.0 Min dioxane) was added slowly at rt, and the reaction mixture was stirredat rt for 2 h. The reaction mixture was concentrated under vacuum. Theresulting crude product was triturated with diethyl ether (15 mL) toafford the title compound. Yield: 88% (150 mg, white solid). ¹H NMR (400MHz, DMSO-d₆): δ 8.55 (s, 2H), 6.25 (br s, 1H), 3.19-3.16 (m, 4H),2.66-2.55 (m, 4H), 2.50-2.46 (m, 4H), 1.97-1.92 (m, 2H). LCMS: (MethodA) 231.0 (M+H), Rt. 2.07 min, 95.97% (Max).

Step 3:6-(1-(4-(5-(cyclopent-1-en-1-yl)pyrimidin-2-yl)piperazin-1-yl)ethyl)quinoxaline

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 1 and5-(cyclopent-1-en-1-yl)-2-(piperazin-1-yl)pyrimidine hydrochloride(white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (dd, J=2.0, -7.2 Hz,2H), 8.45 (s, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 7.91(dd, J=8.8, 2.0 Hz, 1H), 6.15 (s, 1H), 3.77-3.72 (m, 4H), 2.67-2.49 (m,4H), 2.45-2.32 (m, 4H), 1.91 (t, J=7.2 Hz, 2H), 1.43 (d, J=6.80 Hz, 3H).LCMS: (Method B) 387.0 (M+H), Rt. 6.36 min, 98.06% (Max). HPLC: (MethodA) Rt. 3.36 min, 98.14% (Max).

Example 95: Methyl2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

The title compound was synthesized according to the procedure describedfor Example 12, starting from Intermediate 3 and Intermediate 12 (whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.76 (s, 2H), 8.12(d, J=8.00 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J=8.40 Hz, 1H), 3.85 (t,J=4.80 Hz, 4H), 3.79 (s, 3H), 3.70-3.65 (m, 1H), 2.53-2.51 (m, 2H),2.45-2.41 (m, 2H), 1.41 (d, J=6.80 Hz, 3H). LCMS: (Method A) 384.0(M+1), Rt. 2.71 min, 97.0% (Max). HPLC: (Method A) Rt 2.66 min, 97.8%(Max).

Example 96:2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

The title compound was synthesized according to the procedure describedfor Examples 65 and 64, starting from Example 95 (white solid). ¹H NMR(400 MHz, DMSO-d₆: δ 9.38 (s, 1H), 8.70 (s, 2H), 8.27 (d, J=4.40 Hz,1H), 8.11 (d, J=8.00 Hz, 1H), 8.02 (s, 1H), 7.49 (d, J=8.00 Hz, 1H),3.81-3.78 (m, 4H), 3.67-3.64 (m, 1H), 2.73 (d, J=4.40 Hz, 3H), 2.45-2.32(m, 4H), 1.40 (d, J=6.80 Hz, 3H). LCMS: (Method A) 383.0 (M+H), Rt. 2.16min, 99.2% (Max). HPLC: (Method A) Rt 2.11 min, 97.8% (Max).

Example 97:2-(4-(1-(benzo[d]thiazol-5-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

The title compound was synthesized according to the procedure describedfor Examples 65 and 63, starting from Example 95 (white solid). ¹H NMR(400 MHz, DMSO-d₆: δ 9.38 (d, J=1.20 Hz, 1H), 8.44 (d, J=1.20 Hz, 2H),8.11 (d, J=8.40 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J=8.00 Hz, 1H),3.79-3.75 (m, 4H), 3.73-3.66 (m, 1H), 2.96 (s, 6H), 2.45-2.39 (m, 4H),1.40 (d, J=6.40 Hz, 3H). LCMS: (Method A) 397.2 (M+H), Rt. 2.29 min,99.3% (Max). HPLC: (Method A) Rt 2.23 min, 99.3% (Max).

Example 98: Methyl2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of Intermediate 12 (1 g, 3.87 mmol) in dry DMF (10mL), TEA (1.94 mL, 13.95 mmol) and Intermediate 4 (0.24 g, 1.04 mmol)were added at 0° C. The reaction mixture was heated at 100° C. for 12 h.Then the reaction mixture was concentrated under vacuum. The resultingcrude product was purified by column chromatography (2-3% MeOH in DCM aseluent) to afford the title compound (off white solid). ¹H NMR (400 MHz,DMSO-d₆): δ 8.76 (s, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.76 (d, J=7.6 Hz,1H), 6.72 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.82 (t, J=4.8 Hz, 4H), 3.79(s, 3H), 3.50-3.42 (m, 1H), 3.13 (t, J=8.8 Hz, 2H), 2.49-2.44 (m, 2H),2.42-2.33 (m, 2H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (Method A) 369.2(M+H), Rt. 2.96 min, 98.9% (Max). HPLC: (Method A) Rt. 2.95 min, 98.8%(Max).

Example 99:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

Step 1:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylicacid

To a stirred solution of Example 98 (0.840 g, 2.28 mmol) in dioxane (2mL), LiOH (10 M, 1.14 mL, 1.14 mmol) was added at rt and the resultingmixture was stirred for 4 h. The completion of reaction was monitored byTLC. Solvent was evaporated and the product was further dried byazeotropic evaporation of toluene (3×2 mL). The resulting product wasused in the next step without any further purification. Yield: 99.1%(0.90 g, off white solid). LCMS: (Method A) 355 (M+H), Rt. 2.421 min90.06% (Max).

Step 2:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-5-carboxamide

Example 99 was synthesized according to the protocol described forExample 63, starting with2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylicacid and replacing the dimethylamine with a methylamine solution in THF(3.175 ml, 6.35 mmol). The crude product was purified by flashchromatography (2% MeOH in DCM as eluent) to afford the title product(off white solid). LCMS: (Method A) 368 (M+H), Rt 2.413 min 94.23%(Max). HPLC: (Method A), Rt 2.344 min, 96.76% (Max). ¹H NMR (400 MHz,DMSO-d₆): δ 8.70 (s, 2H), 8.27 (d, J=4.4 Hz, 1H), 7.14 (d, J=7.6 Hz,1H), 6.76-6.74 (m, 2H), 4.49 (t, J=8.8 Hz, 2H), 3.78-3.76 (m, 4H), 3.32(s, 1H), 3.14 (t, J=8.8 Hz, 2H), 2.74-2.73 (m, 3H), 2.42-2.36 (m, 4H),1.27 (d, J=6.80 Hz, 3H).

Example 100:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-5-carboxamide

Example 100 was synthesized according to the protocol described forExample 63, starting with 2-(4-(1-(2, 3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylic acid(example 99, step 1). The crude product was purified by flashchromatography (2% MeOH in DCM as eluent) to afford the title product(brown solid). LCMS: (Method A) 382 (M+H), Rt. 2.436 min 98.34% (Max).HPLC: (Method A), Rt. 2.473 min, 97.0% (Max). ¹H NMR: (400 MHz,DMSO-d₆): δ 8.45 (s, 2H), 7.15 (d, J=7.2 Hz, 1H), 6.75 (t, J=7.2 Hz,1H), 4.50 (t, J=8.8 Hz, 2H), 3.77-3.76 (m, 4H), 3.13 (t, J=8.8 Hz, 2H),3.11-2.97 (m, 7H), 1.29-1.27 (m, 3H).

Example 101:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N,N-dimethylpyrimidine-4-carboxamide

Example 101 was synthesized according to the protocol described forExample 100, starting with Example 102. Yield: 62% (321 mg, off whitesolid). ¹H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J=5.2 Hz, 1H), 7.14 (d,J=7.2 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 6.63-6.62 (m, 1H),4.49 (t, J=8.8 Hz, 2H), 3.68-3.67 (m, 4H), 3.36-3.32 (m, 1H), 3.12 (t,J=8.8 Hz, 2H), 2.94 (s, 3H), 2.89 (s, 3H), 2.45-2.33 (m, 4H), 1.27 (d,J=6.40 Hz, 3H). LCMS: (Method A) 382.2 (M+H), Rt. 2.60 min, 97.9% (Max).HPLC: (Method A) Rt 2.55 min, 99.26% (Max).

Example 102: Methyl2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)pyrimidine-4-carboxylate

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 13 and methyl2-chloropyrimidine-4-carboxylate. The crude product was purified byflash chromatography (Elutant: 55-75% EtOAc in pet ether), affording thetitle product. Yield: 68.1% (574 mg, pale yellow thick oil). ¹H NMR (400MHz, DMSO-d₆): δ 8.56-8.55 (m, 1H), 7.14 (d, J=7.6 Hz, 1H), 7.07-7.05(m, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.71 (s, 1H), 4.49 (t, J=8.8 Hz, 2H),3.84 (s, 3H), 3.73-3.72 (m, 4H), 3.37-3.32 (m, 1H), 3.12 (t, J=8.8 Hz,2H), 2.38-2.32 (m, 4H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (Method A) 369.2(M+H), Rt. 2.83 min, 98.25% (Max). HPLC: (Method A) Rt 2.88 min, 98.43%(Max).

Example 103:2-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methylpyrimidine-4-carboxamide

Example 103 was synthesized according to the protocol described forExample 99, starting with Example 102. The crude product was purified byflash chromatography (Elutant: 90% EtOAc in pet ether) to afford thetitle compound (pale yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.69(d, J=4.4 Hz, 1H), 8.52 (d, J=4.8 Hz, 1H), 7.15 (d, J=7.2 Hz, 1H), 7.06(d, J=4.8 Hz, 1H), 6.77 (dd, J=7.6, 1.2 Hz, 1H), 6.73 (s, 1H), 4.51 (t,J=8.4 Hz, 2H), 3.80-3.79 (m, 4H), 3.40-3.38 (m, 1H), 3.14 (t, J=8.8 Hz,2H), 2.79 (d, J=4.80 Hz, 3H), 2.45-2.33 (m, 4H), 1.30 (d, J=6.80 Hz,3H). LCMS: (Method A) 368.2 (M+H), Rt. 2.62 min, 97.33% (Max). HPLC:(Method A) Rt 2.58 min, 99.41% (Max).

Example 104:N-(2-(2-(1-(4-(quinoxalin-6-yl)piperazin-1-yl)ethyl)pyrimidin-5-yl)propan-2-yl)acetamide

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 13 and Intermediate 33(off-White solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (s, 1H), 8.04 (s,1H), 7.15 (d, J=7.6 Hz, 3H), 6.72-6.76 (m, 2H), 4.51 (t, J=8.4 Hz, 2H),3.64-3.65 (m, 4H), 3.14 (t, J=8.4 Hz, 2H), 2.42-2.44 (m, 2H), 2.31-2.33(m, 2H), 1.79 (s, 3H), 1.49 (s, 6H), 1.28 (t, J=6.4 Hz, 3H). LCMS:(Method A) 410.5 (M+H), Rt. 2.58 min, 98.25% (Max). HPLC: (Method A) Rt.2.61 min, 99.51% (Max).

Example 105: Methyl2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylate

To a stirred solution of Intermediate 1 (0.1 g, 0.51 mmol) in dry DMF(5.0 mL), TEA (0.21 mL, 1.5 mmol) and Intermediate 12 (0.115 g, 0.5mmol) were added at rt and the reaction mixture was stirred at 90° C.overnight. The reaction mixture was cooled to rt and concentrated undervacuum. To this resulting crude mixture, water (50 mL) was added andproduct was extracted with DCM (150 mL). Organic layer was dried overanhydrous Na₂SO₄ and concentrated. The crude product was purified byflash chromatography to afford the title compound (pale yellow solid).¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (d, J=5.6 Hz, 2H), 8.77 (s, 2H), 8.10(d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 3.89-3.86 (m,4H), 3.82-3.78 (m, 1H), 3.79 (s, 3H), 2.56-2.57 (m, 2H), 2.46-2.44 (m,2H), 1.44 (d, J=6.4 Hz, 3H). LCMS: (Method A) 379.2 (M+H), Rt. 2.27 min,99.84% (Max). HPLC: (Method A) Rt. 2.33 min, 98.75% (Max).

Example 106:2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidine-5-carboxylicacid

To a stirred solution of Example 105 (1.5 g, 5.96 mmol) in THF (15.0mL), methanol (4.5 mL) and water (4.5 mL), LiOH (330 mg; 7.92 mmol) wasadded at the resulting mixture was stirred for 12 h at rt. Aftercompletion of the reaction, the reaction mixture was acidified to pH 4with a 1N HCl solution. The resulting precipitate was filtered anddissolved in DCM (100 mL). The DCM solution was washed with water (1.0mL), dried over Na₂SO₄ and concentrated to afford the titled compound(yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 12.84 (s, 1H), 8.93 (dd,J=2.0, 7.2 Hz, 2H), 8.73 (s, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.6Hz, 1H), 7.93 (dd, J=2.0, 8.6 Hz, 1H), 3.85 (t, J=5.2 Hz, 4H), 3.79 (d,J=6.8 Hz, 1H), 2.60-2.55 (m, 2H), 2.50-2.43 (m, 2H), 1.44 (d, J=6.80 Hz,3H). LCMS: (Method A) 365.2 (M+H), Rt. 1.84 min, 99.36% (Max). HPLC:(Method A) Rt. 1.88 min, 98.35% (Max).

Example 107:N-(2-(2-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)pyrimidin-5-yl)propan-2-yl)acetamide

The title compound was synthesized according to the procedure describedfor Example 40, starting from Intermediate 2 and Intermediate 33 (paleBrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.95 (d, J=1.6 Hz, 1H), 8.93(d, J=1.6 Hz, 1H), 8.26 (s, 2H), 8.10-8.01 (m, 3H), 7.93 (dd, J=1.6, 8.8Hz, 1H), 3.76-3.69 (m, 5H), 2.57-2.54 (m, 2H), 2.43-2.40 (m, 2H), 1.79(s, 3H), 1.49-1.43 (m, 9H). LCMS: (Method A) 420.2 (M+H), Rt. 2.05 min,97.13% (Max). HPLC: (Method A) Rt. 2.09 min, 98.84% (Max).

Examples 108 and 109:(R)—N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamideand(S)—N-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was synthesized according to the procedure describedfor Example 105, starting from Intermediate 4 and Intermediate 5. Thecrude product was purified by flash chromatography to give the racemicmixture of the title compound.

Both enantiomers were further separated by SFC using the preparativechiral method PA.

The first eluting compound correspond to Example 108 (off white solid).¹H NMR (400 MHz, DMSO-d₆): δ 11.99 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75(d, J=7.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.8 Hz, 2H), 3.38-3.36 (m,1H), 3.35-3.33 (m, 4H), 3.13 (t, J=8.4 Hz, 2H), 2.42-2.38 (m, 4H), 2.07(s, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.31min, 99.4% (Max). HPLC: (Method A) Rt 2.34 min, 99.7% (Max). CHIRALHPLC: (SFC Method K) Rt. 2.81 min, 100% (Max).

The second eluting compound corresponds to Example 109 (white solid). ¹HNMR (400 MHz, DMSO-d₆): δ 12.05 (s, 1H), 7.14 (d, J=7.6 Hz, 1H), 6.75(d, J=7.6 Hz, 1H), 6.70 (s, 1H), 4.49 (t, J=8.8 Hz, 2H), 3.37-3.36 (m,1H), 3.32-3.31 (m, 4H), 3.13 (t, J=8.8 Hz, 2H), 2.41-2.38 (m, 4H), 2.08(s, 3H), 1.27 (d, J=6.40 Hz, 3H). LCMS: (Method A) 374.2 (M+H), Rt. 2.31min, 99.37% (Max). HPLC: (Method A) Rt 2.35 min, 99.59% (Max). CHIRALHPLC: (SFC Method K) Rt. 3.45 min, 99.42% (Max).

Example 110:(N-((5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide

The title compound was synthesized according to the procedure describedfor Example 112, starting from Example 124 (brown thick oil). ¹H NMR(400 MHz, DMSO-d₆): δ 8.70-8.59 (m, 1H), 7.15 (d, J=7.60 Hz, 1H), 6.75(d, J=7.60 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J=8.80 Hz, 2H), 4.37 (d,J=6.00 Hz, 2H), 3.39-3.36 (m, 5H), 3.17-3.11 (m, 2H), 2.42-2.38 (m, 4H),1.83 (s, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 388.3 (M+H), Rt.2.07 min, 96.1% (Max). HPLC: (Method A) Rt 2.09 min, 95.8% (Max).

Example 112:N-((5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methyl)acetamide

To a stirred solution of Example 126 (150 mg, 0.42 mmol) in DCM (2 mL)at 0° C., pyridine (0.07 mL) followed by acetic anhydride (0.06 mL, 0.63mmol) were added. The reaction mixture was stirred at rt overnight. Itwas quenched with water (3 mL) and extracted with DCM (2×5 mL). Thecombined organic layer was dried over anhydrous Na₂SO₄. Afterevaporation of the solvents, the crude product was purified by flashchromatogrypha (eluent: 6-7% MeOH in DCM) affording the title product(yellow solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (dd, J=6.8, 2.4 Hz,2H), 8.64 (t, J=6.0 Hz, 1H), 8.08 (d, J=8.4 Hz, 1H), 8.00 (d, J=1.2 Hz,1H), 7.91-7.89 (m, 1H), 4.37 (d, J=6.0 Hz, 2H), 3.80 (q, J=6.8 Hz, 1H),3.40 (t, J=4.8 Hz, 4H), 2.62-2.58 (m, 4H), 1.83 (s, 3H), 1.42 (d, J=6.80Hz, 3H). LCMS: (Method A) 398.3 (M+H), Rt. 1.55 min, 98.91% (Max). HPLC:(Method A) Rt 1.58 min, 98.72% (Max).

Example 113:(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanolSGN020621-01-00536-031N01:

To a stirred solution of Example 117 (0.21 g, 5.40 mmol) in methanol (4mL), sodium borohydride (62 mg, 1.62 mmol) was added at 0° C. and themixture was stirred at rt for 2 h. It was concentrated under vacuum.EtOAc (10 mL) was added and was washed with water (10 mL), brine (10mL), dried over anhydrous Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography affording the title compound (off whitesolid). ¹H NMR (400 MHz, DMSO-d₆): δ 7.15 (d, J=7.6 Hz, 1H), 6.75 (d,J=7.6 Hz, 1H), 6.71 (s, 1H), 5.86 (t, J=5.6 Hz, 1H), 4.60 (d, J=6.0 Hz,2H), 4.50 (t, J=8.4 Hz, 2H), 3.39-3.37 (m, 5H), 3.13 (t, J=8.8 Hz, 2H),2.43-2.39 (m, 4H), 1.27 (d, J=6.8 Hz, 3H). LCMS: (Method A) 347.2 (M+H),Rt. 2.08 min, 96.5% (Max). HPLC: (Method A) Rt 2.04 min, 96.3% (Max).

Example 114:1-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)ethan-1-ol

The title compound was synthesized according to the procedure describedfor Example 115, starting from Example 113 (white solid). ¹H NMR (400MHz, DMSO-d₆): δ 7.14 (d, J=7.60 Hz, 1H), 6.75 (d, J=7.60 Hz, 1H), 6.70(s, 1H), 6.00 (d, J=4.80 Hz, 1H), 4.86-4.83 (m, 1H), 4.49 (t, J=8.80 Hz,2H), 3.38-3.35 (m, 5H), 3.12 (t, J=8.40 Hz, 2H), 2.41-2.38 (m, 4H), 1.39(d, J=6.40 Hz, 3H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 361.2(M+H), Rt. 2.20 min, 97.8% (Max). HPLC: (Method A) Rt 2.17 min, 98.5%(Max).

Example 115:1-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)ethan-1-ol

Step 1:(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanol

The title compound was obtained following the same procedure asdescribed for Example 113, starting from Example 120. The crude productwas purified by flash chromatography (eluent: 4-5% MeOH in DCM)affording the title compound (brown solid). ¹H NMR (400 MHz, DMSO-d₆): δ8.95-8.96 (m, 2H), 8.10 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (dd,J=8.8, 5.2 Hz, 1H), 5.88 (t, J=6.0 Hz, 1H), 4.61 (d, J=6.0 Hz, 2H), 3.82(q, J=13.6 Hz, 1H), 3.43 (t, J=4.8 Hz, 4H), 2.65-2.60 (m, 2H), 2.60-2.51(m, 2H), 1.44 (d, J=6.80 Hz, 3H). LCMS: (Method A) 357.2 (M+H), Rt. 1.48min, 99.13% (Max).

Step 2:5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carbaldehyde

To a stirred solution of(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanol(0.4 g, 1.12 mmol) in dry DCM (8 mL), Dess-Martin periodinane (571 mg,1.34 mmol) was added at 0° C. and the resulting mixture was stirred atrt for 6 h. After completion of the reaction, the reaction mixture wasquenched with saturated NaHCO₃ solution (10 mL) and extracted with DCM(3×10 mL). The combined organic layer was dried over Na₂SO₄ andconcentrated. The resulting crude product was purified by flashchromatography (3-4% MeOH in DCM), affording the title compound. Yield:93% (350 mg, brown solid). LCMS: (Method A) 355.0 (M+H), Rt. 4.44 min,89% (Max).

Step 3:1-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)ethan-1-ol

To a stirred solution of5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carbaldehyde(100 mg, 1.55 mmol) in dry THF (12 mL) cooled down to −10° C., methylmagnesium chloride (3M in Et₂O, 0.5 mL, 1.41 mmol) was added and themixture was stirred at rt for 3 h. After completion of the reaction, thereaction mixture was quenched with water (2 mL) and concentrated undervacuum. The crude product was dissolved in DCM (10 mL), washed withsaturated NH₄Cl solution (4 mL) and dried over Na₂SO₄. After evaporationof the solvent, the crude product was purified by flash chromatography(eluent: 5-6% MeOH in DCM), affording the title compound (brown solid).¹H NMR (400 MHz, DMSO-d₆): δ 8.94-8.93 (m, 2H), 8.09 (d, J=8.8 Hz, 1H),8.01 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 6.02 (d, J=4.8 Hz, 1H), 4.86 (t,J=5.2 Hz, 1H), 3.81 (t, J=6.4 Hz, 1H), 3.42 (s, 4H), 2.68-2.58 (m, 2H),2.49-2.43 (m, 2H), 1.45-1.40 (m, 6H). LCMS: (Method A) 371.0 (M+H), Rt.1.71 min, 96.06% (Max). HPLC: (Method A) Rt 1.68 min, 97.89% (Max).

Example 116:2-methyl-5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazolequinoxaline

To a stirred solution of Intermediate 2 (0.1 g, 0.4 mmol) in dry DMF (5mL), TEA (0.15 mL, 1.03 mmol) and 2-chloro-5-methyl-1,3,4-thiadiazole(0.066 g, 0.4 mmol) was added at rt and the reaction mixture was stirredat 90° C. overnight. The resulting reaction mixture was cooled to rt andDMF was evaporated under reduced pressure. To the resulting crudemixture, EtOAc (60 mL) was added and washed with water. The organiclayer was dried over Na₂SO₄ and concentrated. The crude product waspurified by flash chromatography to afford the title compound (palebrown solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (dd, J=6.9, 2.0 Hz, 2H),8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 3.82 (q,J=6.4 Hz, 1H), 3.41-3.40 (m, 4H), 2.62-2.60 (m, 4H), 2.51 (s, 3H), 1.44(d, J=6.8 Hz, 3H). LCMS: (Method A) 341.2 (M+H), Rt. 1.69 min, 99.6%(Max). HPLC: (Method A) Rt 1.74 min, 98.6% (Max).

Example 117: Ethyl5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate

To a stirred solution of ethyl 5-chloro-1,3,4-thiadiazole-2-carboxylate(0.25 g, 1.29 mmol) in dry DMF (2.5 mL), K₂CO₃ (0.54 g, 3.89 mmol) andIntermediate 13 (0.59 g, 1.93 mmol) were added at rt. The reactionmixture was stirred overnight at 80° C. It was then concentrated undervacuum. EtOAc (10 mL) was added and the resulting solution was washedwith water (10 mL), brine (10 mL), dried over anhydrous Na₂SO₄ andconcentrated. The crude product was purified by flash chromatography toafford the title compound. Yield: 51% (0.26 g, off white solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.15 (d, J=7.60 Hz, 1H), 6.75 (d, J=7.60 Hz, 1H),6.71 (s, 1H), 4.50 (t, J=8.80 Hz, 2H), 4.33 (q, J=6.80 Hz, 2H), 3.54 (t,J=5.20 Hz, 4H), 3.43-3.41 (m, 1H), 3.13 (t, J=8.40 Hz, 2H), 2.45-2.32(m, 4H), 1.31-1.27 (m, 6H). LCMS: (Method A) 389.2 (M+H), Rt. 2.88 min,95.7% (Max). HPLC: (Method A) Rt 2.81 min, 96.5% (Max).

Example 118:5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N-methyl-1,3,4-thiadiazole-2-carboxamide

The title compound was synthesized according to the procedure describedfor Example 121, starting from Example 117 (brown thick oil). ¹H NMR(400 MHz, DMSO-d₆): δ 8.74 (q, J=4.8 Hz, 1H), 7.16 (d, J=7.2 Hz, 1H),6.76 (d, J=1.2 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.40 Hz, 2H), 3.49 (t,J=4.80 Hz, 4H), 3.43-3.41 (m, 1H), 3.14 (t, J=8.80 Hz, 2H), 2.75 (d,J=4.8 Hz, 3H), 2.53-2.51 (m, 2H), 2.46-2.42 (m, 2H), 1.28 (d, J=6.8 Hz,3H). LCMS: (Method A) 374.0 (M+H), Rt. 2.35 min, 96.4% (Max).

HPLC: (Method A) Rt 2.30 min, 98.2% (Max).

Example 119:5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-N,N-dimethyl-1,3,4-thiadiazole-2-carboxamide

The title compound was synthesized according to the procedure describedfor Example 122, starting from Example 117 (pale yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.15 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H),6.71 (s, 1H), 4.50 (t, J=8.4 Hz, 2H), 3.48 (t, J=4.80 Hz, 4H), 3.39-3.98(m, 4H), 3.13 (t, J=9.20 Hz, 2H), 2.99 (s, 3H), 2.63-2.58 (m, 2H),2.42-2.41 (m, 2H), 1.27 (d, J=6.80 Hz, 3H). LCMS: (Method A) 388.0(M+H), Rt. 2.53 min, 99.3% (Max). HPLC: (Method A) Rt 2.48 min, 98.9%(Max).

Example 120: Ethyl5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxylate

To a stirred solution of Intermediate 2 (2.62 g, 9.40 mmol) in dry DMF(25 mL), TEA (2.8 mL, 20.15 mmol) and ethyl5-chloro-1,3,4-thiadiazole-2-carboxylate (1.2 g, 6.71 mmol) were addedat 0° C. The reaction mixture was stirred at 100° C. overnight. Thereaction mixture was concentrated under vacuum. The resulting crudemixture was dissolved in DCM (35 mL), washed with water (20 mL) anddried over Na₂SO₄. After evaporation of the solvent, the resultingproduct was triturated in Et₂O (2×4 mL), affording the title compound.Yield: 50% (1.3 g, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93(d, J=6.0 Hz, 2H), 8.09 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.91 (d, J=8.8Hz, 1H), 4.33 (q, J=7.2 Hz, 2H), 3.85 (t, J=6.0 Hz, 1H), 3.58 (s, 4H),2.70-2.58 (m, 2H), 2.58-2.50 (m, 2H), 1.44 (d, J=6.4 Hz, 3H), 1.29 (t,J=6.80 Hz, 3H). LCMS: (Method A) 399.2 (M+H), Rt. 2.22 min, 96.96%(Max). HPLC: (Method A) Rt 2.27 min, 96.97% (Max).

Example 121:N-methyl-5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2-carboxamide

To a solution of Example 120 (0.22 g, 0.55 mmol) and methyl amine (2M inTHF, 0.94 mL, 1.83 mmol) in dry toluene (3 mL), bis-trimethyl aluminium1,4 diazabicylco [2,2,2,] octane adduct (241 mg, 0.94 mmol) was added at0° C. and the resulting mixture was heated at 100° C. overnight in asealed tube. After completion of the reaction, solvents are evaporated.Water was added and was extracted with EtOAc (2×8 mL). The combinedorganic layer was dried over Na2SO4 and concentrated. The resultingresidue was purified by MD Autoprep HPLC (Method ?), affording the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.95 (dd,J=7.2, 2.6 Hz, 2H), 8.74 (d, J=4.8 Hz, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.01(s, 1H), 7.91 (dd, J=8.4, 5.2 Hz, 1H), 3.84 (q, J=13.2 Hz, 1H), 3.53 (t,J=4.8 Hz, 4H), 2.75 (d, J=4.4 Hz, 3H), 2.68-2.61 (m, 2H), 2.57-2.51 (m,2H), 1.44 (d, J=6.40 Hz, 3H). LCMS: (Method A) 384.2 (M+H), Rt. 1.74min, 99.16% (Max). HPLC: (Method A) Rt 1.77 min, 99.41% (Max).

Example 122:N,N-dimethyl-5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazole-2carboxamide

Example 122 was synthesized according to the protocol described forExample 121, replacing the methyl amine solution with a dimethyl aminesolution in THF (2M, 3 mL, 6.27 mmol). The crude product was purified byflash chromatography (eluent: 3-4% MeOH in DCM), affording the titlecompound (off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (d, J=5.2Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 7.93-7.83 (m, 1H),3.93-3.76 (m, 1H), 3.54 (t, J=4.8 Hz, 4H), 3.42 (s, 3H), 3.00 (s, 3H),2.65-2.61 (m, 4H), 1.45 (d, J=6.8 Hz, 3H). LCMS: (Method A) 398.0 (M+H),Rt. 1.99 min, 96.23% (Max). HPLC: (Method A) Rt 1.95 min, 96.55% (Max).

Example 123:1-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-N,N-dimethylmethanamine

Step 1:(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methylmethanesulfonate

To a solution of Example 113 (0.1 g, 0.29 mmol) in dry DCM (2 mL), DIPEA(0.15 mL, 0.86 mmol) and methanesulphonyl chloride (0.027 mL, 0.34 mmol)were added at 0° C. and the reaction mixture was stirred at rt for 2 h.Upon completion of reaction, 10% solution of NaHCO₃ (2 mL) was added andthe mixture was stirred for 5 minutes. Two layers were separated and theorganic layer was washed with brine (2 mL) and dried over Na₂SO₄. Theevaporation of the solvent afforded the title compound that was useddirectly in the following step. Yield: 85% (0.12 g, brown thick oil).LCMS: (Method A) 365.0 (M+H), Rt. 2.66 min, 87.5% (Max).

Step 2:1-(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)-N,N-dimethylmethanamine

To a stirred solution of(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methylmethanesulfonate (0.1 g, 0.24 mmol) in dry THF (1 mL), N,N-dimethylaminesolution (2M in THF, 0.12 mL, 1.22 mmol) was added at rt and thereaction mixture was heated to 80° C. for 6 h in sealed tube. Thereaction mixture was cooled to rt and concentrated under vacuum. Theresulting residue was dissolved in DCM (5 ml) and washed with brine (5mL) and dried over anhydrous Na₂SO₄. After evaporation, the crudeproduct was purified by flash chromatography to get the title compound(brown thick oil). ¹H NMR (400 MHz, DMSO-d₆): δ 7.16 (d, J=7.60 Hz, 1H),6.76 (d, J=7.60 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J=8.40 Hz, 2H), 3.62 (s,2H), 3.45-3.36 (m, 5H), 3.14 (t, J=8.40 Hz, 2H), 2.61-2.56 (m, 2H),2.47-2.39 (m, 2H), 2.20 (s, 6H), 1.28 (d, J=6.80 Hz, 3H). LCMS: (MethodA) 374.2 (M+H), Rt. 1.86 min, 97.0% (Max). HPLC: (Method A) Rt 1.89 min,97.2% (Max).

Example 124:(5-(4-(1-(2,3-dihydrobenzofuran-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanamine

The title compound was synthesized according to the procedure describedfor Example 123, starting from Example 113, replacing N,N-dimethylaminesolution with NaN₃ in DMF. The resulting azidomethyl analogue wasreduced with Pd/C (10% wt/wt) under H₂ atmosphere (yellow solid). ¹H NMR(400 MHz, DMSO-d₆): δ 7.14 (d, J=7.60 Hz, 1H), 6.75 (d, J=7.60 Hz, 1H),6.70 (s, 1H), 4.49 (t, J=8.80 Hz, 2H), 3.86 (s, 2H), 3.41-3.34 (m, 5H),3.13 (t, J=8.40 Hz, 2H), 2.42-2.37 (m, 4H), 1.27 (d, J=6.40 Hz, 3H).LCMS: (Method A) 346.3 (M+H), Rt. 1.84 min, 97.7% (Max). HPLC: (MethodA) Rt 1.82 min, 97.9% (Max).

Example 125:N,N-dimethyl-1-(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanamine

The title compound was synthesized according to the procedure describedfor Example 123, starting from Example 115, step 1 product (37 mg, brownsolid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.95 (dd, J=6.8, 2.6 Hz, 2H), 8.10(dd, J=8.4, Hz, 1H), 8.01 (s, 1H), 7.91 (dd, J=8.8, 5.2 Hz, 1H),3.88-3.72 (m, 1H), 3.62 (s, 2H), 3.42 (t, J=4.8 Hz, 5H), 2.63-2.61 (m,3H), 2.19 (s, 6H), 1.44 (d, J=6.8 Hz, 3H). LCMS: (Method A) 384.0 (M+H),Rt. 1.44 min, 96.27% (Max). HPLC: (Method A) Rt 1.43 min, 98.70% (Max).

Example 126:(5-(4-(1-(quinoxalin-6-yl)ethyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)methanamine

The title compound was synthesized according to the procedure describedfor Example 123, starting from Example 115, step 1 product, replacingN,N-dimethylamine solution with NaN₃ in DMF. The resulting azidomethylanalogue was reduced with Pd/C (10% wt/wt) under H₂ atmosphere. Yield:83% (190 mg, off white solid). ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (d,J=5.2 Hz, 2H), 8.08 (d, J=8.8 Hz, 1H), 8.00 (s, 1H), 7.90 (d, J=8.2 Hz,1H), 3.89-3.72 (m, 3H), 3.39 (t, J=4.8 Hz, 4H), 2.65-2.52 (m, 4H), 1.43(d, J=6.4 Hz, 3H). LCMS: (Method A) 356.3 (M+H), Rt. 1.35 min, 97.28%(Max). HPLC: (Method A) Rt 1.37 min, 97.78% (Max).

The examples below were synthesized according to procedures described inthe previous examples. These compounds and their tautomers, enantiomers,and salts are further preferred embodiments of the present invention.

TABLE 2 Config- uration specifi- Ex Structure cation 1H NMR 288

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.90 (d, J = 7.6 Hz, 1H), 7.16 (d,J = 7.6 Hz, 1H), 6.87 (s, 1H), 6.79-6.73 (m, 2H), 6.59 (d, J = 8.0 Hz,1H), 6.50 (s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.40- 3.30 (m, 4H), 3.15(t, J = 8.4 Hz, 2H), 3.15-2.99 (m, 4H), 2.52 (s, 3H), 2.52- 2.49 (m,4H), 1.29 (d, J = 6.40 Hz, 3H). 289

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.26 (s, 1H), 8.51 (s, 1H), 8.06(s, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.76-6.68(m, 2H), 4.50 (t, J = 8.4 Hz, 2H), 3.37-3.32 (m, 5H), 3.13 (t, J = 8.4Hz, 2H), 2.43- 2.39 (m, 4H), 1.29-1.28 (m, 3H). 290

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.04 (d, J = 1.2 Hz, 1H), 8.38 (s,1H), 8.28 (s, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.79 (d, J = 7.2 Hz, 1H),6.75 (s, 1H), 4.54-4.49 (m, 2H), 4.40-4.35 (m, 2H), 3.39-3.29 (m, 5H),3.15 (t, J = 8.4 Hz, 2H), 2.61-2.60 (m, 2H), 2.58-2.48 (m, 2H),1.37-1.30 (m, 6H). 291

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.21 (s, 1H), 7.14 (d, J = 7.2 Hz,1H), 7.25 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H),3.97 (s, 2H), 3.87 (s, 2H), 3.75-3.60 (m, 4H), 3.29-3.27 (m, 1H), 3.13(t, J = 8.8 Hz, 2H), 2.44-2.40 (m, 2H), 2.36- 2.33 (m, 2H), 1.27 (d, J =6.40 Hz, 3H). 292

Chiral HPLC SFC Method D: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 8.68 (s, 2H), 7.15 (d, J = 8.2 Hz, 1H), 6.77-6.73 (m, 2H),4.50 (t, J = 8.8 Hz, 2H), 3.85-3.83 (m, 4H), 3.40-3.37 (m, 1H), 3.21 (s,3H), 3.13 (t, J = 8.7 Hz, 2H), 2.40-2.33 (m, 4H), 1.28 (d, J = 6.8 Hz,3H). 293

Chiral HPLC SFC Method D: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 8.68 (s, 2H), 7.15 (d, J = 8.2 Hz, 1H), 6.77-6.73 (m, 2H),4.50 (t, J = 8.8 Hz, 2H), 3.85-3.83 (m, 4H), 3.40-3.37 (m, 1H), 3.21 (s,3H), 3.13 (t, J = 8.7 Hz, 2H), 2.40-2.33 (m, 4H), 1.28 (d, J = 6.8 Hz,3H). 294

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.05-9.04 (m, 1H), 8.68 (s, 2H),8.43- 8.41 (m, 2H), 7.80 (d, J = 8.4 Hz, 1H), 7.63-7.60 (m, 1H),3.92-3.88 (m, 5H), 3.20 (s, 3H), 2.65-2.50 (m, 4H), 1.44 (d, J = 6.8 Hz,3H) 295

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.67 (s, 2H), 8.12(d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (dd, J = 8.2,1.2 Hz, 1H),3.87-3.85 (m, 4H), 3.68 (d, J = 6.8 Hz, 1H), 3.20 (s, 3H), 2.56-2.33 (m,4H), 1.40 (d, J = 6.8 Hz, 3H). 296

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (s, 1H), 8.70 (s, 1H), 8.56(d, J = 4.4 Hz, 1H), 8.29 (s, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.79 (d, J= 7.6 Hz, 1H), 6.74 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.38-3.37 (m,1H), 3.31-3.30 (m, 4H), 3.14 (t, J = 8.80 Hz, 2H), 2.81 (d, J = 4.40 Hz,3H), 2.59-2.56 (m, 2H), 2.51-2.50 (m, 2H), 1.30 (d, J = 6.40 Hz, 3H).297

Chiral HPLC SFC Method A: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 7.83 (dd, J = 9.6,1.6 Hz, 1H), 7.38 (d, J = 9.6 Hz, 1H),7.16 (d, J = 7.20 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.78 (s, 1H), 4.51(t, J = 8.80 Hz, 2H), 3.74- 3.72 (m, 4H), 3.41-3.38 (m, 1H), 3.30 (s,3H), 3.14 (t, J = 8.80 Hz, 2H), 2.45- 2.41 (m, 4H), 1.30 (d, J = 6.80Hz, 3H). 298

Chiral HPLC SFC Method A: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 7.84 (dd, J = 9.6,1.6 Hz, 1H), 7.38 (d, J = 9.6 Hz, 1H),7.16 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.0 Hz, 1H), 6.73 (s, 1H), 4.51(t, J = 8.8 Hz, 2H), 3.72- 3.69 (m, 4H), 3.51-3.47 (m, 1H), 3.30 (s,3H), 3.14 (t, J = 8.8 Hz, 2H), 2.45- 2.41 (m, 4H), 1.310 (d, J = 6.8 Hz,3H). 299

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.80 (s, 1H), 7.61 (d, J = 5.2 Hz,2H), 7.18-7.16 (m, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.75 (s, 1H),5.46-5.44 (m, 1H), 5.12 (t, J = 6.4 Hz, 1H), 4.54- 4.51 (m, 2H),3.39-3.37 (m, 1H), 3.35 3.20 (m, 4H), 3.15 (t, J = 8.40 Hz, 2H),2.59-2.56 (m, 4H), 1.58 (d, J = 6.40 Hz, 3H), 1.30 (d, J = 6.80 Hz, 3H).300

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (s, 1H), 8.44 (d, J = 1.6 Hz,1H), 7.84 (s, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.78 (d, J = 7.6 Hz, 1H),6.73 (s, 1H), 4.51 (t, J = 8.0 Hz, 2H), 4.32- 4.30 (m, 2H), 3.38-3.32(m, 1H), 3.26 (br s, 4H), 3.17-3.12 (m, 2H), 2.57- 2.55 (m, 2H),2.46-2.32 (m, 2H), 1.33-1.23 (m, 6H). 301

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.68 (s, 2H), 7.16 (d, J = 7.6 Hz,1H), 6.76 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H),3.85-3.84 (m, 4H), 3.38-3.35 (m, 1H), 3.21 (s, 3H), 3.14 (t, J = 8.8 Hz,2H), 2.39- 2.35 (m, 4H), 1.29 (d, J = 6.80 Hz, 3H). 302

Chiral HPLC SFC Method B: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 8.27 (s, 2H), 8.05 (s, 1H), 7.15 (d, J = 5.6 Hz, 1H), 6.77(d, J = 6.8 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.65 (s,4H), 3.17-3.11 (m, 2H), 2.50- 2.42 (m, 2H), 2.35-2.33 (m, 2H), 1.79 (s,3H), 1.49 (s, 6H), 1.28 (d, J = 6.40 Hz, 3H). 303

Chiral HPLC SFC Method B: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 8.27 (s, 2H), 8.02 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H),6.78-6.73 (m, 2H), 4.51 (t, J = 8.8 Hz, 2H), 3.82-3.52 (m, 4H),3.16-3.14 (m, 2H), 2.49-2.29 (m, 4H), 1.80 (d, J = 4.0 Hz, 3H), 1.50 (s,6H), 1.28 (d, J = 5.60 Hz, 3H). 304

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 2H), 7.14 (d, J = 7.6 Hz,1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.4 Hz, 2H),3.74 (t, J = 7.2 Hz, 2H), 3.66 (t, J = 4.8 Hz, 4H), 3.35-3.32 (m, 1H),3.13 (t, J = 8.8 Hz, 2H), 2.46-2.42 (m, 4H), 2.40- 2.33 (m, 2H), 2.06(t, J = 7.6 Hz, 2H), 1.27 (d, J = 6.4 Hz, 3H). 305

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.13 (s, 1H), 8.09(d, J = 6.4 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J = 10.8 Hz, 1H), 3.83 (s,2H), 3.68- 3.66 (m, 5H), 3.11 (t, J = 7.2 Hz, 2H), 2.65-2.63 (m, 2H),2.39-2.37 (m, 4H), 1.40 (d, J = 8.80 Hz, 3H). 306

Chiral HPLC Method D: 1st eluting compound ¹H NMR (400 MHz, DMSO-d₆): δ8.02 (s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.75 (dd, J = 7.6,1.2 Hz, 1H),6.71 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.67- 3.65 (m, 5H), 3.18-3.17(m, 2H), 2.95 (t, J = 6.0 Hz, 2H), 2.56-2.54 (m, 2H), 2.51-2.48 (m, 4H),2.33-2.32 (m, 2H), 1.27 (d, J = 6.8 Hz, 3H). 307

Chiral HPLC Method D: 2nd eluting compound ¹H NMR (400 MHz, DMSO-d₆): δ8.01 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 7.6, 1.2 Hz, 1H),6.71 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.66- 3.64 (m, 5H), 3.13 (t, J =8.8 Hz, 2H), 2.94 (t, J = 6.0 Hz, 2H), 2.55-2.54 (m, 2H), 2.42-2.40 (m,4H), 2.35- 2.33 (m, 2H), 1.27 (d, J = 6.4 Hz, 3H). 308

Chiral HPLC SFC Method C: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.39-8.22 (m, 1H), 8.13 (d, J =8.4 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 3.85-3.76 (m, 4H),3.72-3.63 (m, 1H), 2.75 (d, J = 3.6 Hz, 3H), 2.51-2.36 (m, 4H), 1.41 (d,J = 6.4 Hz, 3H). 309

Chiral HPLC SFC Method C: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.71 (s, 2H), 8.38-8.22 (m, 1H), 8.12 (d, J =8.4 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 7.2 Hz, 1H), 3.82-3.79 (m, 4H),3.72-3.62 (m, 1H), 2.74 (d, J = 4.4 Hz, 3H), 2.51-2.37 (m, 4H), 1.41 (d,J = 6.4 Hz, 3H). 310

Racemic ¹H NMR (400 MHz, CDCl₃): δ 9.13- 9.12 (m, 1H), 8.22-8.18 (m,2H), 7.82 (d, J = 8.4 Hz, 1H), 7.52-7.49 (m, 1H), 7.20 (s, 1H), 6.93 (s,1H), 4.01- 3.96 (m, 1H), 3.84 (s, 3H), 3.05- 2.87 (m, 4H), 2.87-2.75 (m,2H), 2.69- 2.59 (m, 2H), 1.56 (d, J = 6.8 Hz, 3H). 311

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.13 (d, J = 8.4 Hz,1H), 8.03 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.31 (s, 1H), 3.74-3.72 (m,1H), 3.49-3.48 (m, 4H), 3.36 (t, J = 6.8 Hz, 2H), 2.69 (t, J = 6.8 Hz,2H), 2.59- 2.58 (m, 2H), 2.46-2.44 (m, 2H), 1.41 (d, J = 6.40 Hz, 3H).312

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.05 (s, 1H), 7.14 (d, J = 7.6 Hz,1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.53-4.47 (m, 4H), 3.88 (t,J = 5.6 Hz, 2H), 3.65 (t, J = 9.2 Hz, 4H), 3.17- 3.11 (m, 3H), 2.67-2.63(m, 2H), 2.42-2.39 (m, 2H), 1.23-1.23 (m, 3H). 313

Chiral HPLC Method R: 2nd eluting compound ¹H NMR: (400 MHz, DMSO-d₆): δ11.71 (s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.70(s, 1H), 4.51 (t, J = 8.4 Hz, 2H), 3.45-3.30 (m, 1H), 3.17-3.12 (m, 6H),2.47- 2.34 (m, 4H), 1.26 (d, J = 6.8 Hz, 3H), 314

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (d, J = 6.8 Hz, 1H), 8.58 (d,J = 6.8 Hz, 1H), 8.12 (d, J = 10.8 Hz, 1H), 8.03 (s, 1H), 7.80-7.65 (m,1H), 7.51- 7.49 (m, 1H), 3.90-3.78 (m, 4H), 3.73-3.63 (m, 1H), 3.40-3.35(m, 2H), 2.80-2.73 (m, 2H), 2.30-2.13 (m, 4H), 1.41 (d, J = 8.80 Hz,3H). 315

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (s, 1H), 8.58 (s, 1H), 8.45(d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.67-7.52(m, 1H), 3.99-3.73 (m, 1H), 3.43-3.36 (m, 6H), 2.80-2.77 (m, 2H),2.67-2.57 (m, 2H), 2.44-2.38 (m, 2H), 1.45 (d, J = 5.6 Hz, 3H). 316

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.18 (s, 1H), 8.13(d, J = 2.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.48-4.43(m, 2H), 4.12-4.12 (m, 1H), 3.69-3.68 (m, 6H), 3.19-3.18 (m, 2H),2.73-2.72 (m, 1H), 2.68-2.67 (m, 1H), 2.45-2.34 (m, 2H), 2.08 (s, 3H),1.40 (d, J = 4.40 Hz, 3H). 317

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.12 (d, J = 8.4 Hz,1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.49 (br s,1H), 3.67- 3.63 (m, 5H), 3.58-3.56 (m, 2H), 3.44- 3.44 (m, 2H),2.72-2.67 (m, 4H), 2.51-2.51 (m, 2H), 2.39-2.37 (m, 4H), 1.40 (d, J =6.40 Hz, 3H). 318

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.12 (d J = 8.4 Hz,1H), 8.04-8.02 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H), 3.67-3.64 (m, 5H),3.31 (s, 2H), 2.68-2.66 (m, 2H), 2.59-2.58 (m, 2H), 2.38-2.32 (m, 4H),2.32 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). 319

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (d, J = 3.2 Hz, 1H), 8.44 (d,J = 8.0 Hz, 2H), 8.32 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63-7.61 (m,1H), 4.43 (s, 2H), 4.38 (s, 2H), 3.88 (d, J = 6.4 Hz, 1H), 3.80-3.70 (m,4H), 2.69-2.45 (m, 4H), 1.44 (d, J = 6.40 Hz, 3H). 320

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.31 (s, 1H), 7.14 (d, J = 7.2 Hz,1H), 6.75 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.4 Hz, 2H),4.43 (s, 2H), 4.38 (s, 2H), 3.60-3.72 (m, 4H), 3.17-3.10 (m, 3H),2.45-2.33 (m, 4H), 1.27 (d, J = 6.8 Hz, 3H). 321

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.83 (s, 1H), 9.06-9.04 (m, 1H),8.50- 8.41 (m, 4H), 7.81 (d, J = 8.8 Hz, 1H), 7.68-7.56 (m, 1H),3.91-3.85 (m, 1H), 3.75-3.62 (m, 4H), 2.62-2.58 (m, 2H), 2.47-2.43 (m,2H), 2.01 (s, 3H), 1.23 (d, J = 10.8 Hz, 3H). 322

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.22-9.20 (m, 1H), 8.01-7.99 (m,2H), 7.15 (d, J = 7.6 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H),4.51 (t, J = 8.4 Hz, 2H), 3.60-3.45 (m, 4H), 3.31- 3.28 (m, 1H), 3.14(t, J = 8.4 Hz, 2H), 2.51-2.42 (m, 2H), 2.38-2.30 (m, 2H), 1.28 (d, J =6.4 Hz, 3H). 323

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.18 (s, 2H), 7.14 (d, J = 7.6 Hz,1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.86 (t, J = 5.6 Hz, 1H),4.51-4.49 (m, 2H), 3.98-3.93 (m, 2H), 3.69- 3.62 (m, 2H), 3.61-3.53 (m,4H), 3.17- 3.11 (m, 2H), 2.46-2.39 (m, 2H), 2.38-2.30 (m, 2H), 1.27 (d,J = 6.8 Hz, 3H). 324

Racemic ¹H NMR: (400 MHz, DMSO-d₆): δ 11.73 (s, 1H), 9.04 (d, J = 2.8Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.61 (t, J= 3.6 Hz, 1H), 3.91-3.89 (m, 1H), 3.19-3.16 (m, 4H), 2.62-2.60 (m, 2H),2.50-2.46 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H). 325

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 11.71 (s, 1H), 9.04 (d, J = 8.4 Hz,1H), 8.47-8.47 (m, 2H), 8.01 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 3.69 (q,J = 6.4 Hz, 1H), 3.24-3.12 (m, 4H), 2.68-2.64 (m, 2H), 2.43-2.40 (m,2H), 1.39 (d, J = 6.8 Hz, 3H). 326

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.12 (d, J = 8.0 Hz,1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 4.54 (s, 2H),3.89 (t, J = 5.6 Hz, 2H), 3.70-3.60 (m, 5H), 2.71- 2.60 (m, 2H),2.50-2.30 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H). 327

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.59-8.57 (m, 2H),8.12 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H),3.79-3.52 (m, 7H), 2.45-2.36 (m, 6H), 2.07 (t, J = 7.6 Hz, 2H), 1.41 (d,J = 6.4 Hz, 3H). 328

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.30(t, J = 5.2 Hz, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J= 8.4 Hz, 1H), 3.82-3.78 (m, 4H), 3.67-3.63 (m, 1H), 3.28-3.21 (m, 4H),2.46-2.36 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H), 1.10 (t, J = 7.2 Hz, 3H).329

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.46 (s, 2H), 7.15 (d, J = 7.6 Hz,1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.4 Hz, 1H),3.66-3.62 (m, 4H), 3.12 (t, J = 8.4 Hz, 2H), 2.42- 2.44 (m, 2H),2.37-2.28 (m, 2H), 1.32 (s, 6H), 1.28 (t, J = 6.4 Hz, 3H). 330

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.06 (s, 1H), 8.59 (s, 2H), 8.46(d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.62 (dd, J = 7.4, 4.3Hz, 1H), 3.41- 3.35 (m, 1H), 3.78-3.62 (m, 6H), 2.62-2.58 (m, 2H),2.45-2.38 (m, 4H), 2.10-2.00 (m, 2H), 1.45 (d, J = 5.6 Hz, 3H). 331

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.11 (d, J = 8.4 Hz,1H), 8.01 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 4.01-4.09 (m, 1H),3.71-3.63 (m, 3H), 3.32-3.29 (m, 4H), 3.17 (s, 1H), 2.94 (t, J = 5.6 Hz,2H), 2.44-2.42 (m, 4H), 1.39 (d, J = 6.4 Hz, 3H). 332

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.11 (d, J = 8.0 Hz,1H), 8.01 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 3.69-3.66 (m, 1H),3.39-3.36 (m, 2H), 3.32-3.25 (m, 5H), 3.17 (s, 1H), 2.61 (t, J = 5.2 Hz,2H), 2.59-2.41 (m, 4H), 2.31 (s, 3H), 1.39 (d, J = 6.8 Hz, 3H). 333

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.12 (d, J = 8.0 Hz,1H), 8.01 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 4.48-4.45 (m, 2H),3.70-3.64 (m, 3H), 3.36-3.33 (m, 4H), 2.55-2.60 (m, 2H), 2.49-2.39 (m,4H), 2.07-2.03 (m, 3H), 1.40 (d, J = 6.4 Hz, 3H). 334

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.11 (d, J = 8.4 Hz,1H), 8.01 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 4.51-4.39 (m, 1H),3.69-3.66 (m, 1H), 3.54-3.48 (m, 4H), 3.32-3.28 (m, 4H), 2.73-2.70 (m,2H), 2.59-2.52 (m, 6H), 2.46-2.40 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). 335

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.93 (s, 1H), 8.78 (d, J = 4.4 Hz,1H), 8.04 (d, J = 4.4 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.74 (d, J =13.6 Hz, 1H), 6.77 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.51 (t, J = 4.8Hz, 4H), 3.38- 3.35 (m, 1H), 3.13 (t, J = 8.8 Hz, 2H), 2.61-2.49 (m,2H), 2.44-2.40 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H). 336

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.05-9.05 (m, 1H), 8.44 (d, J = 8.4Hz, 2H), 8.26 (s, 2H), 8.02 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.63-7.61(m, 1H), 3.87-3.86 (m, 1H), 3.71-3.69 (m, 4H), 2.60-2.59 (m, 2H),2.47-2.46 (m, 2H), 1.78 (s, 3H), 1.49 (s, 6H), 1.44 (d, J = 6.4 Hz, 3H).337

Racemic ¹HNMR (400 MHz, DMSO-d₆): δ 9.04 (t, J = 2.4 Hz, 1H), 8.44 (d, J= 8.4 Hz, 2H), 8.06 (s, 1H), 7.80 (d, J = 12.0 Hz, 1H), 7.63-7.62 (m,1H), 4.53 (s, 2H), 3.90-3.88 (m, 3H), 3.71- 3.69 (m, 4H), 2.69-2.66 (m,2H), 2.59- 2.58 (m, 2H), 2.46-2.45 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H).338

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.05 (d, J = 2.0 Hz, 1H), 8.72 (s,2H), 8.45 (d, J = 8.0 Hz, 2H), 8.29-8.27 (m, 1H), 7.80 (d, J = 8.4 Hz,1H), 7.62- 7.61 (m, 1H), 3.82-3.73 (m, 5H), 2.74- 2.73 (m, 3H),2.67-2.49 (m, 4H), 1.45 (d, J = 5.6 Hz, 3H). 339

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.05-9.04 (m, 1H), 8.72 (s, 2H),8.45 (d, J = 8.8 Hz, 2H), 8.04 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 8.4 Hz,1H), 7.63- 7.60 (m, 1H), 4.05-4.01 (m, 1H), 3.90- 3.87 (m, 1H),3.82-3.79 (m, 4H), 2.67-2.58 (m, 2H), 2.49-2.32 (m, 2H), 1.44 (d, J =6.8 Hz, 3H), 1.13 (d, J = 6.4 Hz, 6H). 340

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.05-9.01 (m, 1H), 8.74 (s, 2H),8.45 (d, J = 8.4 Hz, 2H), 8.32-8.30 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H),7.63-7.60 (m, 1H), 4.71 (t, J = 5.2 Hz, 1H), 3.90- 3.87 (m, 1H),3.82-3.79 (m, 4H), 3.50-3.45 (m, 2H), 3.32-3.26 (m, 2H), 2.62-2.58 (m,2H), 2.50-2.45 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H). 341

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.05-9.01 (m, 1H), 8.72 (s, 2H),8.45 (d, J = 8.4 Hz, 2H), 8.32-8.30 (m, 1H), 7.81 (d, J = 8.4 Hz, 1H),7.63-7.60 (m, 1H), 3.90-3.89 (m, 1H), 3.82-3.79 (m, 4H), 3.26-3.22 (m,2H), 2.66- 2.58 (m, 2H), 2.45-2.32 (m, 2H), 1.44 (d, J = 6.8 Hz, 3H),1.09 (t, J = 7.2 Hz, 3H). 342

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (s, 2H), 7.14 (d, J = 6.0 Hz,1H), 6.77-6.72 (m, 2H), 6.51-6.49 (m, 1H), 4.50-4.50 (m, 4H), 4.36-4.34(m, 1H), 3.70-3.69 (m, 5H), 3.42-3.40 (m, 2H), 3.31-3.10 (m, 2H),2.33-2.31 (m, 4H), 1.25 (d, J = 13.2 Hz, 3H). 343

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.16 (d, J = 7.6 Hz, 1H), 6.76 (d,J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.26-4.24 (m,2H), 3.51- 3.45 (m, 4H), 3.44-3.42 (m, 1H), 3.14 (t, J = 8.4 Hz, 2H),2.45-2.44 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H).344

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (d, J = 4.0 Hz, 1H), 7.17-7.15(m, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 9.2 Hz,2H), 3.42- 3.40 (m, 5H), 3.14 (t, J = 8.4 Hz, 2H), 2.70-2.68 (m, 3H),2.43-2.40 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). 345

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.94 (s, 1H), 8.79(d, J = 4.4 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 4.8 Hz, 2H),7.52 (d, J = 8.0 Hz, 1H), 3.72-3.68 (m, 1H), 3.56- 3.54 (m, 4H),2.59-2.56 (m, 4H), 1.42 (d, J = 6.4 Hz, 3H). 346

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.25 (s, 2H), 8.11(d, J = 8.0 Hz, 1H), 8.02-7.95 (m, 2H), 7.50 (d, J = 8.4 Hz, 1H),3.67-3.64 (m, 5H), 2.50-2.32 (m, 4H), 1.78 (s, 3H), 1.48 (s, 6H), 1.40(d, J = 6.0 Hz, 3H). 347

Racemic 1H NMR (400 MHz, DMSO-d₆): δ 10.12 (s, 1H), 7.40 (s, 1H), 7.31(s, 1H), 7.14 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H), 6.70 (s,1H), 4.51 (t, J = 8.8 Hz, 2H), 3.90 (s, 2H), 3.52- 3.49 (m, 5H), 3.15(t, J = 8.0 Hz, 2H), 2.36-2.30 (m, 4H), 1.25 (d, J = 5.20 Hz, 3H). 348

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.15 (d, J = 7.6 Hz, 1H), 6.75 (d,J = 7.2 Hz, 1H), 6.70 (s, 1H), 4.68-4.58 (m, 2H), 4.51 (t, J = 8.8 Hz,2H), 4.04- 4.01 (m, 1H), 3.93-3.91 (m, 2H), 3.34- 3.31 (m, 2H),3.24-3.21 (m, 4H), 3.14 (t, J = 8.8 Hz, 2H), 2.44-2.41 (m, 2H),2.37-2.33 (m, 2H), 2.13-2.09 (m, 3H), 1.27 (d, J = 6.4 Hz, 3H). 349

Racemic 1H NMR (400 MHz, DMSO-d₆): δ 8.92 (s, 1H), 7.15 (d, J = 7.6 Hz,1H), 6.77-6.72 (m, 2H), 4.93 (s, 2H), 4.74 (s, 2H), 4.50 (t, J = 8.4 Hz,2H), 3.71-3.68 (m, 4H), 3.17-3.11 (m, 3H), 2.46-2.40 (m, 2H), 2.37-2.31(m, 2H), 1.28 (d, J = 6.80 Hz, 3H). 350

Racemic 1H NMR (400 MHz, DMSO-d₆): δ 9.05-9.04 (m, 1H), 8.44 (d, J = 8.4Hz, 2H), 8.29 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.63-7.60 (m, 1H), 4.92(s, 2H), 4.73 (s, 2H), 3.88-3.86 (m, 1H), 3.74-3.72 (m, 4H), 2.60-2.56(m, 2H), 2.46-2.43 (m, 2H), 1.43 (d, J = 6.40 Hz, 3H). 351

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 7.79 (s, 1H), 7.15(d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.76 (s,2H), 4.51 (t, J = 8.8 Hz, 2H), 3.59-3.53 (m, 4H), 3.34- 3.32 (m, 1H),3.13 (t, J = 8.4 Hz, 2H), 2.42-2.39 (m, 2H), 2.33-2.30 (m, 2H), 1.27 (d,J = 6.80 Hz, 3H). 352

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 9.05 (d, J = 2.0 Hz,1H), 8.47-8.45 (m, 2H), 7.82-7.78 (m, 2H), 7.63-7.59 (m, 1H), 4.75 (s,2H), 3.87-3.85 (m, 1H), 3.71-3.61 (m, 4H), 2.50-2.48 (m, 2H), 2.47-2.43(m, 2H), 1.43 (d, J = 6.4 Hz, 3H). 353

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.39 (s, 1H), 8.12(d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.78 (s, 1H), 7.49 (d, J = 8.0 Hz,1H), 4.76 (s, 2H), 3.64-3.58 (m, 5H), 2.51-2.47 (m, 2H), 2.38-2.34 (m,2H), 1.40 (d, J = 6.40 Hz, 3H). 354

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.14 (s, 1H), 9.39 (s, 1H), 8.12(d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.40 (s,1H), 7.33 (s, 1H), 3.89 (s, 2H), 3.61 (d, J = 6.8 Hz, 1H), 3.59-3.55 (m,4H), 2.45-2.40 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H). 355

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.98 (d, J = 8.4 Hz, 1H), 7.85 (s,1H), 7.39 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 3.68-3.66 (m, 1H),3.56-3.42 (m, 4H), 2.79 (s, 3H), 2.71-2.67 (m, 2H), 2.61-2.53 (m, 2H),2.48-2.42 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H). 356

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.59 (s, 1H), 7.97 (d, J = 8.4 Hz,1H), 7.84 (s, 1H), 7.65 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.40 (s, 1H),4.60 (s, 2H), 3.60-3.55 (m, 1H), 3.40-3.35 (m, 4H), 3.34 (s, 3H),2.41-2.34 (m, 4H), 1.38 (d, J = 6.8 Hz, 3H). 357

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.97 (d, J = 8.4 Hz,1H), 7.85 (s, 1H), 7.71 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.92-3.75 (m,4H), 3.64-3.60 (m, 1H), 3.42-3.35 (m, 2H), 2.79 (s, 3H), 2.79-2.75 (m,2H), 2.49-2.35 (m, 4H), 1.39 (d, J = 6.4 Hz, 3H). 358

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.72 (s, 2H), 8.29 (d, J = 4.4 Hz,1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.39 (dd, J = 8.4,1.2 Hz,1H), 3.80 (t, J = 4.8 Hz, 4H), 3.64-3.60 (m, 1H), 2.79 (s, 3H),2.76-2.74 (m, 3H), 2.49-2.47 (m, 2H), 2.42-2.37 (m, 2H), 1.39 (d, J =6.8 Hz, 3H). 359

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.19 (s, 1H), 7.97 (d, J = 8.4 Hz,1H), 7.84 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 5.31-5.30 (m, 1H), 4.49 (t,J = 5.2 Hz, 2H), 3.89-3.76 (m, 2H), 3.70-3.66 (m, 2H), 3.66-3.55 (m,3H), 3.42- 3.40 (m, 4H), 3.35-3.31 (m, 2H), 2.79 (s, 3H), 2.68-2.68 (m,2H), 2.51- 2.51 (m, 2H), 1.40 (d, J = 5.2 Hz, 3H). 360

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (s, 2H), 8.04 (s, 1H), 7.97(d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.40 (dd, J = 8.4,1.2 Hz, 1H), 3.67(t, J = 4.4 Hz, 4H), 3.62-3.57 (m, 1H), 2.79 (s, 3H), 2.49-2.47 (m, 2H),2.40-2.34 (m, 2H), 1.79 (s, 3H), 1.49 (s, 6H), 1.39 (d, J = 6.8 Hz, 3H).361

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.92 (t, J = 1.6 Hz, 1H), 8.78 (s,2H), 7.15 (d, J = 7.6 Hz, 1H), 6.77-6.72 (m, 2H), 4.50 (t, J = 8.0 Hz,2H), 4.09- 4.05 (m, 2H), 3.80 (t, J = 4.8 Hz, 4H), 3.36 (t, J = 8.0 Hz,1H), 3.13 (t, J = 8.8 Hz, 2H), 2.53-2.47 (m, 2H), 2.46- 2.33 (m, 2H),1.28 (d, J = 6.40 Hz, 3H). 362

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (s, 2H), 7.14 (d, J = 7.6 Hz,1H), 6.77-6.72 (m, 2H), 4.50 (t, J = 6.8 Hz, 2H), 3.76-3.74 (m, 4H),3.49-3.46 (m, 4H), 3.15-3.12 (m, 2H), 2.50-2.44 (m, 2H), 2.38-2.30 (m,7H), 2.25- 2.10 (m, 3H), 1.28 (d, J = 6.4 Hz, 3H). 363

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.43 (s, 2H), 7.15 (d, J = 7.6 Hz,1H), 6.76 (d, J = 8.8 Hz, 1H), 6.73 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H),3.76 (t, J = 10.0 Hz, 4H), 3.59 (d, J = 8.0 Hz, 4H), 3.54-3.45 (m, 4H),3.42-3.38 (m, 1H), 3.18-3.11 (m, 2H), 2.52-2.50 (m, 2H), 2.38-2.33 (m,2H), 1.28 (s, 3H). 364

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.29 (s, 1H), 8.12(d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.92 (s,2H), 4.73 (s, 2H), 3.74-3.60 (m, 5H), 2.45-2.51 (m, 2H), 2.41-2.38 (m,2H), 1.41 (d, J = 6.8 Hz, 3H). 365

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.97-12.71 (m, 1H), 7.15 (d, J =7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 6.23-5.89 (m, 1H),4.50 (t, J = 6.8 Hz, 2H), 4.29-4.21 (m, 2H), 3.15 (t, J = 6.8 Hz, 2H),3.33-3.32 (m, 1H), 3.11-3.07 (m, 4H), 2.50- 2.39 (m, 4H), 1.29-1.26 (m,6H). 366

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.49-12.37 (m, 1H), 8.24-8.23 (m,1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H),6.17- 5.79 (m, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.32-3.30 (m, 1H),3.17-3.10 (m, 2H), 3.10-3.00 (m, 4H), 2.75-2.65 (m, 3H), 2.50-2.45 (m,2H), 2.42-2.35 (m, 2H), 1.27 (d, J = 6.4 Hz, 3H). 367

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 9.38 (s, 1H), 8.11(dd, J = 8.0, 3.6 Hz, 1H), 8.01 (s, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.49(d, J = 6.4 Hz, 1H), 6.39 (s, 1H), 4.59 (s, 2H), 3.67- 3.60 (m, 1H),3.40-3.30 (m, 4H), 2.70-2.67 (m, 1H), 2.40-2.35 (m, 2H), 2.20-2.10 (m,1H), 1.39 (d, J = 2.8 Hz, 3H). 368

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.59 (s, 1H), 9.06 (d, J = 4.0 Hz,1H), 8.45 (t, J = 5.2 Hz, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.65 (s, 1H),7.62 (dd, J = 8.0, 4.4 Hz, 1H), 6.41 (s, 1H), 4.60 (s, 2H), 3.85 (q, J =6.8 Hz, 1H), 3.40-3.30 (m, 4H), 2.65-2.57 (m, 2H), 2.50-2.40 (m, 2H),1.44 (d, J = 6.8 Hz, 3H). 369

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.56 (s, 1H), 7.96 (d, J = 8.0 Hz,1H), 7.83 (d, J = 1.2 Hz, 1H), 7.78 (s, 1H), 7.38 (dd, J = 8.4, 1.6 Hz,1H), 4.75 (s, 2H), 3.59-3.57 (m, 5H), 2.79 (s, 3H), 2.52-2.49 (m, 2H),2.34-2.31 (m, 2H), 1.37 (d, J = 6.80 Hz, 3H). 370

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.14 (d, J = 7.6 Hz, 1H), 6.93-6.90(m, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 4.49 (t, J = 8.8 Hz,2H), 4.19 (s, 2H), 4.06 (s, 2H), 3.64 (br s, 4H), 3.38-3.33 (m, 1H),3.12 (t, J = 8.8 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.33- 2.30 (m, 4H),1.27 (d, J = 6.40 Hz, 3H).-1H missing. 371

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.15 (d, J = 7.6 Hz, 1H), 6.77-6.72(m, 2H), 4.50 (t, J = 8.4 Hz, 2H), 4.36 (s, 2H), 4.20 (s, 2H), 3.88 (s,3H), 3.71 (br s, 4H), 3.38-3.34 (m, 1H), 3.13 (t, J = 8.0 Hz, 2H),2.36-2.33 (m, 4H), 1.28 (d, J = 6.80 Hz, 3H). 372

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.46 (s, 1H), 7.16 (d, J = 7.2 Hz,1H), 6.77-6.72 (m, 2H), 4.60 (s, 2H), 4.51 (t, J = 8.8 Hz, 2H), 4.42 (s,2H), 3.58 (br s, 4H), 3.38 (t, J = 6.4 Hz, 1H), 3.18-3.12 (m, 2H),2.40-2.34 (m, 4H), 1.28 (d, J = 6.80 Hz, 3H). 373

Chiral HPLC SFC Method C: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.38-8.27 (m, 1H), 8.12 (d, J =8.4 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.88-3.75 (m, 4H),3.73-3.63 (m, 1H), 3.28-3.19 (m, 2H), 2.67-2.53 (m, 2H), 2.45-2.39 (m,2H), 1.41 (d, J = 6.80 Hz, 3H), 1.10 (t, J = 7.20 Hz, 3H). 374

Chiral HPLC SFC Method C: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.72 (s, 2H), 8.31 (t, J = 5.2 Hz, 1H), 8.12(d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 3.89-3.76(m, 4H), 3.75-3.60 (m, 1H), 3.30-3.21 (m, 2H), 2.67-2.52 (m, 2H),2.47-2.37 (m, 2H), 1.41 (d, J = 6.40 Hz, 3H), 1.10 (t, J = 7.20 Hz, 3H).375

Chiral HPLC SFC Method E: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.06 (t, J = 2.4 Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.07 (s,1H), 7.80 (d, J = 12.0 Hz, 1H), 7.63 (s, 1H), 4.54 (s, 2H), 3.90-3.88(m, 3H), 3.71-3.69 (m, 4H), 2.67-2.65 (m, 2H), 2.59-2.58 (m, 4H), 1.44(d, J = 6.4 Hz, 3H). 376

Chiral HPLC SFC Method E: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.04 (t, J = 2.4 Hz, 1H), 8.44 (d, J = 8.4 Hz, 2H), 8.06 (s,1H), 7.80 (d, J = 12.0 Hz, 1H), 7.63-7.62 (m, 1H), 4.53 (s, 2H),3.90-3.88 (m, 3H), 3.71- 3.69 (m, 4H), 2.69-2.66 (m, 2H), 2.59- 2.58 (m,2H), 2.46-2.45 (m, 2H), 1.43 (d, J = 6.4 Hz, 3H). 377

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.14 (d, J = 7.6 Hz, 1H), 6.75 (d,J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.13 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H),4.13 (t, J = 6.0 Hz, 2H), 3.69 (t, J = 5.6 Hz, 2H), 3.32- 0.00 (m, 1H),3.13 (t, J = 8.8 Hz, 2H), 3.10-3.00 (m, 4H), 2.95 (s, 3H), 2.46-2.33 (m,4H), 1.26 (d, J = 6.80 Hz, 3H). 378

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.30 (d, J = 5.6 Hz,1H), 8.11 (d, J = 7.2 Hz, 1H), 7.49 (d, J = 6.4 Hz, 1H), 6.13 (s, 1H),4.15-4.12 (m, 2H), 3.71-3.68 (m, 2H), 3.63- 3.62 (m, 1H), 3.10-3.05 (m,4H), 2.95 (s, 3H), 2.6-2.5 (m, 2H), 2.44- 2.42 (m, 2H), 1.40-1.39 (m,3H). 379

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.74 (d, J = 2.0 Hz, 2H), 8.33 (t,J = 4.8 Hz, 1H), 7.15 (d, J = 7.20 Hz, 1H), 6.76 (d, J = 7.60 Hz, 1H),6.72 (s, 1H), 4.73-4.72 (m, 1H), 4.53-4.49 (m, 2H), 3.79-3.78 (m, 4H),3.49-3.48 (m, 2H), 3.38-3.36 (m, 1H), 3.31-3.28 (m, 2H), 3.16-3.11 (m,2H), 2.46-2.44 (m, 2H), 2.37-2.33 (m, 2H), 1.29-1.28 (m, 3H). 380

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.37 (s, 1H), 8.72 (s, 2H), 8.31(t, J = 8.4Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J =8.0 Hz, 1H), 4.70 (t, 1H, J = 5.6 Hz), 3.79-3.78 (m, 4H), 3.49-3.45 (m,3H), 3.28-3.25 (m, 2H), 2.50-2.36 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H). 381

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.05 (d, J = 5.6 Hz, 1H), 7.15 (d,J = 7.6 Hz, 1H), 6.76 (dd, J = 7.6, 1.2 Hz, 1H), 6.72 (s, 1H), 6.03 (d,J = 5.6 Hz, 1H), 4.50 (t, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.68 (t, J =4.8 Hz, 4H), 3.37- 3.35 (m, 1H), 3.13 (t, J = 8.4 Hz, 2H), 2.43-2.39 (m,2H), 2.36-2.32 (m, 2H), 1.28 (d, J = 6.8 Hz, 3H). 382

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (d, J = 3.2 Hz, 1H), 7.15 (d,J = 7.2 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J =8.8 Hz, 2H), 3.91 (s, 3H), 3.62-3.65 (m, 4H), 3.14 (t, J = 8.8 Hz, 2H),2.45-2.25 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H). 383

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.66 (s, 1H), 7.15 (d, J = 7.6 Hz,1H), 6.87 (s, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 5.70 (d, J =6.0 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.62-3.52 (m, 4H), 3.34 (s, 1H),3.14 (t, J = 8.4 Hz, 2H), 2.73-2.68 (m, 3H), 2.38- 2.30 (m, 4H), 1.28(d, J = 6.4 Hz, 3H). 384

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.71 (t, J = 1.6 Hz, 1H), 7.20 (d,J = 4.0 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.2 Hz, 1H),6.71 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.62-3.34 (m, 4H), 3.32 (s, 1H),3.14 (t, J = 8.8 Hz, 2H), 2.79 (d, J = 4.4 Hz, 3H), 2.33- 2.29 (m, 4H),1.28 (d, J = 6.8 Hz, 3H). 385

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.08-8.98 (m, 1H), 8.21 (s, 1H),8.11 (s, 1H), 8.05-7.85 (m, 1H), 7.61-7.45 (m, 1H), 4.27 (s, 2H), 4.20(s, 2H), 3.92-3.40 (m, 5H), 2.69-2.38 (m, 4H), 1.44 (d, J = 7.2 Hz, 3H).386

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 7.81 (s, 1H), 7.15(d, J = 7.60 Hz, 1H), 6.76 (d, J = 7.20 Hz, 1H), 6.71 (s, 1H), 4.93 (dd,J = 13.80, 7.20 Hz, 1H), 4.51 (t, J = 8.80 Hz, 2H), 3.57 (t, J = 4.80Hz, 4H), 3.29 (s, 1H), 3.14 (t, J = 8.40 Hz, 2H), 2.44- 2.40 (m, 2H),2.34-2.30 (m, 2H), 1.46 (d, J = 7.20 Hz, 3H), 1.26 (t, J = 8.00 Hz, 3H).387

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.39 (s, 1H), 8.12(d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.50 (d, J = 8.4 Hz,1H), 4.93 (dd, J = 13.6, 6.8 Hz, 1H), 3.64-3.60 (m, 5H), 2.51-2.47 (m,2H), 2.38-2.34 (m, 2H), 1.45 (d, J = 6.8 Hz, 3H), 1.40 (d, J = 6.8 Hz,3H). 388

Chiral HPLC SFC Method F: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 8.58 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.69(s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.82-3.81 (m, 4H), 3.63-3.62 (m, 1H),3.37-3.36 (m, 2H), 2.79 (s, 3H), 2.79-2.75 (m, 2H), 2.44-2.41 (m, 2H),2.42-2.41 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). 389

Chiral HPLC SFC Method F: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 8.58 (s, 1H), 7.97 (d, J = 8.0 Hz, 1H), 7.85 (s, 1H), 7.69(s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 3.82-3.80 (m, 4H), 3.63-3.62 (m, 1H),3.38-3.36 (m, 2H), 2.79 (s, 3H), 2.79-2.77 (m, 2H), 2.48-2.46 (m, 2H),2.41-2.39 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). 390

Chiral HPLC SFC Method F: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 10.89-10.39 (m, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H),7.77 (s, 1H), 7.38 (d, J = 8.0 Hz, 1H), 4.74 (s, 2H), 3.67-3.52 (m, 5H),2.79 (s, 3H), 2.47- 2.40 (m, 2H), 2.40-2.34 (m, 2H), 1.38 (d, J = 6.8Hz, 3H). 391

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.11 (s, 1H), 7.15 (d, J = 7.2 Hz,1H), 6.76 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H),4.31 (s, 2H), 3.75-3.65 (m, 4H), 3.40-3.30 (m, 2H), 3.60-3.50 (m, 1H),3.20-3.10 (m, 4H), 2.30-2.20 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H). 392

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.93 (s, 1H), 8.13-8.11 (m, 2H),8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.30- 4.25 (m, 2H), 3.70-3.60(m, 4H), 3.60-3.55 (m, 1H), 3.40-3.35 (m, 2H), 3.20-3.10 (m, 2H),2.40-2.37 (m, 4H), 1.40 (d, J = 6.40 Hz, 3H). 393

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 8.73 (s, 1H),7.77-7.65 (m, 2H), 7.40 (d, J = 8.4 Hz, 1H), 3.67- 3.55 (m, 1H),3.34-3.24 (m, 4H), 2.52-2.46 (m, 4H), 2.09 (s, 3H), 1.38 (d, J = 4.0 Hz,3H). 394

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.58 (s, 1H),7.76-7.69 (m, 3H), 7.41 (dd, J = 8.0,1.6 Hz, 1H), 3.82-3.72 (m, 4H),3.64 (t, J = 6.8 Hz, 1H), 3.38-3.33 (m, 2H), 2.78 (t, J = 6.4 Hz, 2H),2.41-2.37 (m, 4H), 1.38 (d, J = 6.8 Hz, 3H). 395

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 8.73 (s, 1H), 7.73(d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.4 Hz, 1H), 3.68-3.63 (m, 1H),3.37-3.36 (m, 4H), 2.50-2.40 (m, 4H), 2.10 (s, 3H), 1.38 (d, J = 6.8 Hz,3H). 396

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 1H), 8.59 (s, 1H), 7.74(s, 1H), 7.71 (d, J = 4.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 3.88-3.80(m, 4H), 3.66- 3.61 (m, 1H), 3.40-3.30 (m, 2H), 2.78 (t, J = 6.4 Hz,2H), 2.40-2.30 (m, 4H), 1.39 (d, J = 6.80 Hz, 3H). 397

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.50 (s, 1H), 7.81 (s, 1H), 7.15(d, J = 8.0 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.72 (s, 1H), 4.51 (t, J= 8.8 Hz, 2H), 3.56 (d, J = 4.4 Hz, 4H), 3.14 (t, J = 8.4 Hz, 2H),2.65-2.55 (m, 3H), 2.50- 2.48 (m, 2H), 1.46 (s, 6H), 1.27 (d, J = 6.4Hz, 3H). 398

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.50 (s, 1H), 9.39 (s, 1H), 8.12(d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.81 (s, 1H), 7.50 (d, J = 7.2 Hz,1H), 3.64-3.58 (m, 5H), 2.50-2.42 (m, 2H), 2.40-2.30 (m, 2H), 1.46 (s,6H), 1.40 (d, J = 6.8 Hz, 3H). 399

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.08 (s, 1H), 7.42 (d, J = 4.0 Hz,2H), 7.14 (d, J = 7.2 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.69 (s, 1H),4.50 (t, J = 8.8 Hz, 2H), 4.02-4.00 (m, 1H), 3.54- 3.51 (m, 5H), 3.13(t, J = 8.8 Hz, 2H), 2.36-2.32 (m, 4H), 1.30-1.28 (m, 6H). 400

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.55 (s, 2H), 8.04 (d, J = 2.4 Hz,1H), 7.78 (d, J = 2.4 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.76 (d, J =7.6 Hz, 1H), 6.72 (s, 1H), 4.50 (dt, J = 8.8, 2.4 Hz, 2H), 3.84 (d, J =2.8 Hz, 3H), 3.70- 3.65 (m, 4H), 3.38-3.30 (m, 1H), 3.13 (t, J = 8.8 Hz,2H), 2.50-2.40 (m, 2H), 2.39-2.30 (m, 2H), 1.28 (d, J = 8.8 Hz, 3H). 401

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.395 (s, 1H), 8.57 (s, 2H), 8.13(d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 7.80 (s, 1H), 7.52 (d, J= 7.2 Hz, 1H), 3.85 (s, 3H), 3.75-3.70 (m, 4H), 3.68-3.63 (m, 1H),2.45-2.40 (m, 4H), 1.42 (d, J = 6.8 Hz, 3H). 402

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.94 (s, 1H), 9.38 (s, 1H), 8.59(s, 2H), 8.11 (d, J = 8.0 Hz, 2H), 8.02 (s, 1H), 7.85 (s, 1H), 7.50 (d,J = 8.0 Hz, 1H), 3.71-3.63 (m, 5H), 2.51-2.49 (m, 2H), 2.42-2.39 (m,2H), 1.45 (d, J = 2.4 Hz, 3H). 403

Chiral HPLC SFC Method G: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.38 (s, 1H), 8.57 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02(s, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 3.83-3.81 (m, 4H),3.67-3.66 (m, 1H), 3.35-3.33 (m, 2H), 2.77 (t, J = 5.2 Hz, 2H),2.46-2.40 (m, 4H), 1.40 (d, J = 5.2 Hz, 3H). 404

Chiral HPLC SFC Method G: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.58 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.03(s, 1H), 7.68 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 3.83-3.81 (m, 4H),3.68-3.67 (m, 1H), 3.35 (t, J = 6.8 Hz, 2H), 2.78 (t, J = 6.8 Hz, 2H),2.47-2.40 (m, 4H), 1.41 (d, J = 6.40 Hz, 3H). 405

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.92 (s, 1H), 7.81 (d, J = 8.8 Hz,1H), 7.59 (d, J = 8.4 Hz, 1H), 4.30 (s, 3H), 3.71-3.69 (m, 1H),3.37-3.35 (m, 4H), 2.56-2.53 (m, 2H), 2.46-2.43 (m, 2H), 2.10 (s, 3H),1.40 (d, J = 6.8 Hz, 3H). 406

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.05 (s, 1H), 12.04 (s, 1H), 8.10(d, J = 6.4 Hz, 2H), 7.60 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 3.66 (t, J= 6.4 Hz, 1H), 3.38-3.34 (m, 4H), 2.68-2.57 (m, 2H), 2.47-2.44 (m, 2H),2.10 (s, 3H), 1.37 (d, J = 6.4 Hz, 3H). 407

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.42-7.37 (m, 1H), 7.13 (d, J = 7.2Hz, 1H), 6.74 (d, J = 7.20 Hz, 1H), 6.69 (s, 1H), 4.50 (t, J = 8.4 Hz,2H), 3.45- 3.39 (m, 4H), 3.29-3.27 (m, 1H), 3.16-3.11 (m, 2H), 2.41-2.30(m, 4H), 1.25 (d, J = 6.40 Hz, 3H). 408

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.51 (s, 1H), 7.64 (s, 1H), 7.14(d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.70 (s, 1H), 6.40 (s,1H), 4.729 (t, J = 6.8 H, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.32-3.19 (m,5H), 3.13 (t, J = 8.8 Hz, 2H), 2.45-2.33 (m, 4H), 1.39 (s, 3H), 1.27 (d,J = 6.8 Hz, 3H). 409

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 9.39 (s, 1H), 8.12(d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.66 (s, 1H), 7.50 (d, J = 8.4 Hz,1H), 6.42 (s, 1H), 4.75-4.70 (m, 1H), 3.65-3.60 (m, 1H), 3.36-3.34 (m,4H), 2.41-2.39 (m, 4H), 1.41 (d, J = 6.0 Hz, 3H), 1.40 (s, 3H). 410

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.06 (s, 1H), 9.37 (s, 1H), 8.10(d, J = 8.4 Hz, 1H), 8.00 (s, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.45-7.40(m, 2H), 4.02-4.00 (m, 1H), 3.61-3.59 (m, 5H), 2.46-2.44 (m, 2H),2.35-2.33 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.28 (d, J = 6.8 Hz, 3H).411

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.05 (s, 1H), 9.39 (s, 1H), 8.12(d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.46-7.42(m, 2H), 3.62-3.60 (m, 5H), 2.47-2.46 (m, 2H), 2.36-2.35 (m, 2H), 1.39(d, J = 6.8 Hz, 3H), 1.30 (s, 6H). 412

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.50 (s, 1H), 7.66 (s, 1H), 7.15(d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 6.39 (s,1H), 4.51 (t, J = 8.4 Hz, 2H), 3.40-3.30 (m, 5H), 3.14 (t, J = 8.4 Hz,2H), 2.49-2.40 (m, 2H), 2.38-2.30 (m, 2H), 1.41 (s, 6H), 1.28 (d, J =6.4 Hz, 3H). 413

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 10.48 (s, 1H), 9.38 (s, 1H), 8.11(d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.64 (s, 1H), 7.49 (d, J = 8.0 Hz,1H), 6.38 (s, 1H), 3.63-3.58 (m, 1H), 3.40-3.30 (m, 4H), 2.39-2.33 (m,4H), 1.39-1.35 (m, 9H). 414

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.39 (s, 1H), 7.15 (d, J = 7.6 Hz,1H), 6.76 (d, J = 7.2 Hz, 1H), 6.71 (s, 1H), 5.90 (s, 1H), 4.93 (s, 1H),4.51 (t, J = 8.4 Hz, 2H), 3.57-3.10 (m, 5H), 3.26- 2.96 (m, 9H),2.51-2.39 (m, 4H), 1.27 (d, J = 6.0 Hz, 3H). 415

Racemic ¹H NMR (400 MHz, CDCl₃): δ 7.12 (d, J = 7.6 Hz, 1H), 6.75 (d, J= 7.2 Hz, 1H), 6.68 (s, 1H), 4.89 (d, J = 5.6 Hz, 1H), 3.34-3.31 (m,4H), 3.24 (s, 1H), 2.78-2.76 (m, 2H), 2.51-2.43 (m, 4H), 2.10 (s, 3H),1.39 (d, J = 4.0 Hz, 3H), 1.28 (d, J = 6.0 Hz, 3H). 416

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.69 (s, 1H), 7.11(d, J = 7.6 Hz, 1H), 6.75(d, J = 7.2 Hz, 1H), 6.68 (s, 1H), 4.89-4.87(m, 1H), 3.80-3.79 (m, 4H), 3.38-3.24 (m, 5H), 2.80-2.67 (m, 4H),2.46-2.43 (m, 1H), 2.37-2.33 (m, 1H), 1.39-1.37 (m, 3H), 1.28 (d, J =6.8 Hz, 3H). 417

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 1H), 7.87 (d, J = 8.8 Hz,1H), 7.77 (s, 1H), 7.69 (s, 1H), 7.46 (d, J = 8.4 Hz, 1H), 3.80-3.78 (m,4H), 3.65 (t, J = 6.4 Hz, 1H), 3.37-3.34 (m, 3H), 2.77 (t, J = 6.8 Hz,2H), 2.52- 2.49 (m, 2H), 2.40-2.37 (m, 2H), 1.38 (d, J = 6.4 Hz, 3H).418

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.24 (s, 1H), 7.15 (d, J = 6.8 Hz,1H), 6.81 (s, 2H), 4.59 (t, J = 8.80 Hz, 2H), 3.95 (s, 3H), 3.86-3.76(m, 4H), 3.51-3.40 (m, 1H), 3.21 (t, J = 8.00 Hz, 2H), 2.58-2.51 (m,4H), 1.31- 1.26 (m, 3H). 419

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.73 (s, 2H), 7.15 (d, J = 7.2 Hz,1H), 6.76 (d, J = 7.2 Hz, 1H), 6.73 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H),3.82-3.80 (m, 4H), 3.39-3.37 (m, 1H), 3.14 (t, J = 8.8 Hz, 2H),2.40-2.34 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). 420

Chiral HPLC SFC Method F: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.13-8.10 (m, 2H), 8.02 (s, 1H), 7.50 (d, J =8.4 Hz, 1H), 4.31- 4.30 (m, 2H), 3.80-3.71 (m, 4H), 3.64 (q, J = 5.6 Hz1H), 3.48-3.45 (m, 2H), 3.15-3.12 (m, 2H), 2.40-2.37 (m, 4H), 1.40 (d, J= 5.6 Hz, 3H). 421

Chiral HPLC SFC Method F: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.13-8.10 (m, 2H), 8.02 (s, 1H), 7.50 (d, J =8.4 Hz, 1H), 4.31- 4.30 (m, 2H), 3.80-3.71 (m, 4H), 3.65 (q, J = 5.6 Hz1H), 3.48-3.45 (m, 2H), 3.15-3.12 (m, 2H), 2.40-2.37 (m, 4H), 1.40 (d, J= 5.6 Hz, 3H). 422

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.35 (s, 1H), 7.15 (d, J = 7.2 Hz,1H), 6.76 (d J = 7.1 Hz, 1H), 6.71 (ms, 1H), 6.00 (s, 1H), 4.51 (t, J =8.8 Hz, 2H), 3.35-3.3 (m, 1H), 3.19-3.14 (m, 5H), 3.12-2.95 (m, 6H),2.41-2.33 (m, 4H), 1.55 (d, J = 6.0 Hz, 3H). 423

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (s, 1H), 7.16 (d, J = 7.2 Hz,1H), 6.74 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.60 (s, 1H), 4.50 (t, J =8.6 Hz, 2H), 4.42 (s, 2H), 3.58-3.56 (m, 4H), 3.34-3.33 (m, 2H), 3.13(t, J = 8.0 Hz, 2H), 2.40 (t, J = 39.2 Hz, 4H), 1.28 (d, J = 6.8 Hz,3H). 424

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.71 (s, 2H), 7.14 (d, J =7.2 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.48 (t, J = 6.8Hz, 2H), 3.81-3.79 (m, 4H), 3.36 (q, J = 6.8 Hz, 1H), 3.13 (t, J = 8.4Hz, 2H), 2.45-2.39 (m, 4H), 1.28 (d, J = 6.4 Hz, 3H). 425

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.48-12.44 (m, 1H), 8.24-7.77 (m,1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.71 (s, 1H),6.24- 5.81 (m, 1H), 4.74-4.72 (q, J = 6.8 Hz, 1H), 4.51 (t, J = 8.4 Hz,2H), 3.48- 3.45 (m, 2H), 3.34-3.30 (m, 1H), 3.18- 3.14 (m, 4H),3.10-3.04 (m, 4H), 2.50-2.34 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). 426

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d,J = 1.2 Hz, 1H), 6.71 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.22 (t, J =4.8 Hz, 2H), 3.72 (t, J = 4.8 Hz, 2H), 3.39-3.34 (m, 1H), 3.16-3.09 (m,6H), 2.96 (s, 3H), 2.51-2.33 (m, 4H), 1.28 (d, J = 6.80 Hz, 3H). 427

Racemic ¹H NMR (400 MHz, DMSO-d₆): 8.38 (d, J = 4.4 Hz, 1H), 7.55 (d, J= 4.4 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 7.2 Hz, 1H), 6.73(s, 1H), 4.51 (t, J = 8.8 Hz, 2H), 4.03 (s, 3H), 3.47-3.38 (m, 4H),3.36-3.34 (m, 1H), 3.16 (t, J = 8.4 Hz, 2H), 2.43-2.34 (m, 4H), 1.29 (d,J = 6.8 Hz, 3H). 428

Racemic ¹HNMR (400 MHz, DMSO-d₆): δ 11.70 (s, 1H), 7.62 (d, J = 5.6 Hz,1H), 7.15 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 5.6 Hz, 1H), 6.76 (d, J =8.4 Hz, 1H), 6.72 (s, 1H), 4.50 (t, J = 8.4 Hz, 2H), 3.48-4.34 (m, 4H),3.13 (t, J = 8.8 Hz, 2H), 2.49-2.33 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H).429

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.07 (s, 1H), 7.96 (d, J = 8.4 Hz,1H), 7.83 (s, 1H), 7.38 (dd, J = 8.6, 1.6 Hz, 1H), 4.22-4.10 (m, 2H),3.90 (s, 1H), 3.71-3.69 (m, 4H), 3.60 (q, J = 6.8 Hz, 1H), 3.40-3.25 (m,2H), 3.06 (t, J = 6.8 Hz, 2H), 2.79 (s, 3H), 2.45- 2.33 (m, 4H), 1.38(d, J = 6.8 Hz, 3H). 430

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.11 (d, J = 8.4 Hz,1H), 8.07 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.51-7.48 (dd, J = 8.4, 1.6Hz, 1H), 4.18-4.08 (m, 2H), 3.90 (s, 1H), 3.72- 3.64 (m, 5H), 3.36-3.29(m, 2H), 3.06 (t, J = 6.4 Hz, 2H), 2.52-2.39 (m, 4H), 1.39 (d, J = 6.80Hz, 3H). 431

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.08 (s, 1H), 7.14 (d, J = 7.6 Hz,1H), 6.75 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.50 (t, J = 8.8 Hz, 2H),4.22-4.10 (m, 2H), 3.91 (s, 1H), 3.69-3.67 (m, 4H), 3.40-3.30 (m, 2H),3.18-3.05 (m, 5H), 2.50-2.31 (m, 4H), 1.27 (d, J = 6.4 Hz, 3H). 432

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.40 (s, 1H), 8.77 (s, 2H), 8.33(s, 1H), 8.13 (d, J = 7.2 Hz, 1H), 8.04 (s, 1H), 7.74 (s, 1H), 7.52 (d,J = 6.8 Hz, 1H), 6.54 (s, 1H), 3.37-3.67 (m, 5H), 2.68-2.34 (m, 4H),1.43 (d, J = 4.8 Hz, 3H). 433

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.16 (s, 2H), 8.12(d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.00 (q, J= 6.8 Hz, 2H), 3.64-3.62 (m, 5H), 2.45-2.39 (m, 4H), 1.40 (d, J = 6.8Hz, 3H), 1.28 (t, J = 6.8 Hz, 3H). 434

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.15 (s, 2H), 8.12(d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 4.44-4.43(m, 1H), 3.63-3.61 (m, 5H), 2.45-2.39 (m, 4H), 1.40 (d, J = 6.8 Hz, 3H),1.21 (d, J = 6.0 Hz, 6H). 435

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.27 (s, 2H), 8.12(d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 1H), 4.73(q, J = 8.8 Hz, 2H), 3.65-3.64 (m, 5H), 2.45-2.39 (m, 4H), 1.40 (d, J =6.8 Hz, 3H). 436

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.00 (s, 1H), 7.09 (d, J = 7.6 Hz,1H), 6.73 (d, J = 7.6 Hz, 1H), 6.63 (s, 1H), 3.37-3.33 (m, 4H), 2.96 (s,2H), 2.50-2.35 (m, 4H), 2.09 (s, 3H), 1.40 (s, 3H), 1.39(s, 3H), 1.27(d, J = 6.4 Hz, 3H). 437

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.70 (s, 1H), 7.10(d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.2 Hz, 1H), 6.65 (s, 1H), 3.80-3.79(s, 4H), 3.37-3.36 (d, J = 4.0 Hz, 1H), 2.96 (s, 2H), 2.37-2.34 (m, 4H),1.40 (d, J = 2.8 Hz, 6H), 1.28 (d, J = 6.8 Hz, 3H). 438

Chiral HPLC SFC Method I: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 7.14 (d, J = 7.2 Hz, 1H), 6.73 (d, J = 8.0 Hz, 1H), 6.70 (s,1H), 6.46 (s, 2H), 4.52-4.48 (m, 2H), 3.37-3.365 (m, 1H), 3.19-3.11 (m,6H), 2.45-2.36 (m, 4H), 1.25 (d, J = 6.8 Hz, 3H). 439

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.03 (s, 1H), 7.61-7.59 (m, 2H),7.32 (d, J = 9.6 Hz, 1H), 3.62-3.60 (m, 1H), 3.47-3.35 (m, 4H), 2.6 (s,3H), 2.45-2.41 (m, 4H), 2.10 (s, 3H), 1.37 (d, J = 6.8 Hz, 3H). 440

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 1H), 7.70 (s, 1H),7.60-7.58 (m, 2H), 7.32 (d, J = 8.0 Hz, 1H), 3.88-3.75 (m, 4H), 3.60 (q,J = 6.8 Hz, 1H), 3.43-3.33 (m, 2H), 2.78 (t, J = 6.8 Hz, 2H), 2.60 (s,3H), 2.38- 2.22 (m, 4H), 1.37 (d, J = 6.8 Hz, 3H). 441

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.67 (s, 2H), 7.59-7.57 (m, 2H),7.31 (dd, J = 8.6, 0.8 Hz, 1H), 3.84 (t, J = 5.2 Hz, 4H), 3.61-3.59 (m,1H), 3.20 (s, 3H), 2.59 (s, 3H), 2.50-2.48 (m, 2H), 2.41-2.37 (m, 2H),1.36 (d, J = 6.8 Hz, 3H). 442

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.10 (s, 1H), 7.60-7.58 (m, 2H),7.31 (d, J = 8.4 Hz, 1H), 4.30 (s, 2H), 3.75- 3.66 (m, 4H), 3.58-3.56(m, 1H), 3.47 (t, J = 6.0 Hz, 2H), 3.14 (t, J = 6.8 Hz, 2H), 2.60 (s,3H), 2.44-2.29 (m, 4H), 1.37 (d, J = 6.4 Hz, 3H). 443

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.47 (d, J = 2.4 Hz,1H), 8.13 (d, J = 6.4 Hz, 1H), 8.03 (s, 1H), 7.86 (d, J = 6.8 Hz, 1H),7.50 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 9.6 Hz, 1H), 3.75-3.67 (m, 5H),3.14 (s, 3H), 2.55-2.51 (m, 2H), 2.44-2.41 (m, 2H), 1.41 (d, J = 6.4 Hz,3H). 444

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.47 (d, J = 1.6 Hz, 1H), 7.97 (d,J = 8.4 Hz, 1H), 7.87-7.85 (m, 2H), 7.39 (d, J = 7.2 Hz, 1H), 6.91 (d, J= 9.2 Hz, 1H), 3.67-3.61 (m, 5H), 3.13 (s, 3H), 2.79 (s, 3H), 2.55-2.55(m, 2H), 2.45-2.43 (m, 2H), 1.39 (d, J = 6.4 Hz, 3H). 445

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.69-8.67 (m, 2H), 7.97 (d, J = 8.4Hz, 1H), 7.85 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 3.92-3.86 (m, 4H),3.64-3.63 (m, 1H), 3.21 (s, 3H), 2.80 (s, 3H), 2.43- 2.40 (m, 4H), 1.39(d, J = 6.8 Hz, 3H). 446

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.84 (s, 1H), 7.16 (d, J = 7.6 Hz,1H), 6.77 (d, J = 7.6 Hz, 1H), 6.73 (s, 1H), 6.33 (s, 1H), 4.51 (t, J =8.8 Hz, 1H), 3.54-3.51 (m, 4H), 3.42-3.20 (m, 1H), 3.14 (t, J = 8.8 Hz,2H), 2.40- 2.30 (m, 4H), 1.29 (d, J = 6.8 Hz, 3H). 447

Chiral HPLC SFC Method G: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.67 (s, 2H), 8.11 (d, J = 8.4 Hz, 1H), 8.02(s, 1H), 7.50 (dd, J = 8.4, 1.6 Hz 1H), 3.87-3.85 (m, 4H), 3.68 (q, d, J= 6.8 Hz, 1H), 3.20 (s, 3H), 2.56-2.41 (m, 4H), 1.42 (d, J = 6.8 Hz,3H). 448

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.76 (s, 1H), 8.67 (s, 1H), 7.16 d,J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 2H), 4.80-4.70 (m, 2H), 4.40-4.38(m, 1H), 4.15 (t, J = 4.4 Hz, 3H), 3.75 (m, 1H), 2.85-2.75 (m, 10H),1.92 (t, J = 5.6 Hz, 2H), 1.61 (d, J = 6.8 Hz, 3H). 449

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 7.69 (s, 1H),7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.50(t, J = 8.8 Hz, 2H), 3.81-3.76 (m, 4H), 3.38-3.37 (m, 3H), 3.13 (t, J =8.8 Hz, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.42-2.38 (m, 4H), 1.28 (d, J =6.80 Hz, 3H). 450

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.60 (s, 1H),8.12 (d, J = 8.4 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H),3.84-3.71 (m, 4H), 3.68 (d, J = 7.2 Hz, 1H), 3.32 (d, J = 4.4 Hz, 2H),2.96 (s, 3H), 2.46-2.33 (m, 2H), 1.41 (d, J = 6.8 Hz, 3H), 1.19 (s, 6H).451

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.58 (s, 1H), 8.12(d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.0 Hz, 1H), 3.88-3.77(m, 4H), 3.64-3.63 (m, 1H), 3.55-3.44 (m, 2H), 2.94 (s, 3H), 2.87-2.84(m, 2H), 2.45-2.42 (m, 2H), 1.40 (d, J = 6.8 Hz, 3H). 452

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.16 (s, 2H), 7.14 (d, J =7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 4.90 (q, J = 7.2 Hz1H), 4.50 (t, J = 8.8 Hz, 2H), 3.67 (s, 3H), 3.59 (t, J = 4.8 Hz, 3H),3.13 (t, J = 8.4 Hz, 2H), 2.46-2.42 (m, 2H), 2.36-2.32 (m, 2H), 1.47 (d,J = 6.80 Hz, 3H), 1.28 (t, J = 6.4 Hz, 3H). 453

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.26 (s, 2H), 8.04 (q, J =4.4 Hz, 1H), 7.15 (d, J = 7.6 Hz, 3H), 6.75 (d, J = 7.6 Hz, 1H), 6.71(s, 1H), 4.58 (q, J = 6.8 Hz, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.60-3.58(m, 4H), 3.14 (t, J = 8.8 Hz, 2H) 2.60 (d, J = 8.8 Hz, 3H), 2.45- 2.33(m, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.28 (t, J = 8.0 Hz, 3H). 454

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (s, 2H), 7.15 (d, J =7.2 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72 (s, 1H), 4.91 (d, J = 6.8Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.67 (s, 3H), 3.61-3.58 (m, 4H),3.33-3.29 (m, 1H), 3.14 (t, J = 8.4 Hz, 2H), 2.46-2.42 (m, 4H), 1.48 (d,J = 6.8 Hz, 3H), 1.26 (t, J = 6.8 Hz, 3H),. 455

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.15 (s, 2H), 8.05 (s, 1H),7.15 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.72 (s, 1H), 4.58(q, J = 6.4 Hz, 1H), 4.51 (t, J = 8.8 Hz, 2H), 3.59- 3.57 (m, 4H),3.18-3.11 (m, 3H), 2.67- 2.59 (m, 3H), 2.35-2.34 (m, 4H), 1.38 (d, J =6.4 Hz, 3H), 1.28 (d, J = 6.4 Hz, 3H). 456

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.72 (s, 2H),8.12 (d, J = 8.0 Hz, 1H), 8.02 (s, 1H), 7.50 (dd, J = 8.2, 1.2 Hz, 2H),3.83 (t, J = 4.8 Hz, 4H), 3.65 (q, J = 6.8 Hz, 1H), 2.46- 2.42 (m, 4H),1.41 (d, J = 6.8 Hz, 3H). 457

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.39 (s, 2H),8.11 (d, J = 8.8 Hz, 1H), 8.02 (s, 1H), 7.50 (d, J = 8.2 Hz, 1H),3.70-3.66 (m, J = 4.8 Hz, 5H), 2.50-2.33 (m, 4H), 1.40 (d, J = 6.4 Hz,3H). 458

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.75-8.74 (m,2H), 8.12 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 1.2 Hz, 1H), 7.82 (s, 1H),7.50 (dd, J = 8.4, 1.2 Hz, 1H), 7.26 (s, 1H), 3.81 (t, J = 4.8 Hz, 4H),3.67 (q, J = 6.4 Hz, 1H), 2.56-2.39 (m, 4H), 1.41 (d, J = 6.8 Hz, 3H).459

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 1H), 8.11 (d, J = 5.2 Hz,1H), 7.70 (s, 1H), 6.97 (d, J = 4.0 Hz, 1H), 6.75 (s, 1H), 3.83-3.50 (m,7H), 3.48 (q, J = 5.8 Hz, 1H), 3.38-3.28 (m, 2H), 2.80-2.77 (m, 2H),2.51-2.45 (m, 2H), 2.39-2.33 (m, 2H), 1.29 (d, J = 6.8 Hz, 3H). 460

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.57 (s, 1H), 8.40 (s, 1H), 7.84(s, 1H), 7.70 (s, 1H), 6.74 (s, 1H), 3.81-3.79 (m, 4H), 3.71-3.69 (m,1H), 3.38- 3.36 (m, 2H), 2.78 (t, J = 6.4 Hz, 2H), 2.51 (s, 3H),2.51-2.46 (m, 4H), 1.40 (d, J = 6.80 Hz, 3H). 461

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.40 (s, 1H), 7.84 (s, 1H), 6.75(s, 1H), 3.72-3.51 (m, 1H), 3.36 (t, J = 4.8 Hz, 4H), 2.51 (s, 3H),2.47-2.42 (m, 4H), 2.12 (s, 3H), 1.40 (d, J = 6.8 Hz, 3H). 462

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.61 (s, 2H), 8.12(d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.32 (s,2H), 3.83-3.81 (m, 4H), 3.68-3.66 (m, 1H), 2.55-2.38 (m, 4H), 1.40 (d, J= 6.8 Hz, 3H). 463

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.62 (s, 2H), 7.33 (s, 2H),7.15 (d, J = 7.6 Hz, 1H), 6.77-6.72 (m, 2H), 4.50 (t, J = 8.8 Hz, 2H),3.80-3.80 (m, 4H), 3.38-3.36 (m, 1H), 3.13 (t, J = 8.4 Hz, 2H),2.46-2.35 (m, 4H), 1.28 (d, J = 6.8 Hz, 3H). 464

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.57 (s, 2H), 8.12(dd, J = 8.2,1.2 Hz, 1H), 8.03 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H),7.37-7.36 (m, 1H), 3.85-3.82 (m, 4H), 3.68 (q, J = 6.4 Hz, 1H), 2.56 (s,3H), 2.45-2.41 (m, 4H), 1.41 (d, J = 6.4 Hz, 3H). 465

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (s, 2H), 7.36 (d, J =5.2 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 6.76 (d, J = 7.6 Hz, 1H), 6.72(s, 1H), 4.50 (t, J = 8.8 Hz, 2H), 3.82-3.79 (m, 4H), 3.52- 3.32 (m,1H), 3.13 (t, J = 8.8 Hz, 2H), 2.48-2.37 (m, 7H), 1.28 (d, J = 6.4 Hz,3H). 466

Racemic ¹H NMR (400 MHz, CDCl₃): δ 7.98 (s, 1H), 7.19 (s, 1H), 5.07-5.05(m, 1H), 3.70-3.65 (m, 4H), 3.49-3.43 (m, 1H), 3.30-3.18 (m, 1H),2.99-2.93 (m, 1H), 2.77-2.74 (m, 4H), 2.34 (s, 3H), 1.55 (d, J = 3.6 Hz,3H), 1.27 (d, J = 5.20 Hz, 3H). 467

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.30 (s, 1H), 8.99 (s, 1H), 8.24(s, 1H), 7.15 (d, J = 7.2 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.73 (s,1H), 4.51 (t, J = 8.8 Hz, 2H), 3.85-3.84 (m, 4H), 3.38 (q, J = 6.8 Hz,1H), 3.14 (t, J = 8.4 Hz, 2H), 2.50-2.34 (m, 4H), 1.29 (d, J = 6.4 Hz,3H). 468

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.41 (s, 1H), 8.52 (s, 2H), 8.12(d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.94 (m,1H), 3.80- 3.79 (m, 4H), 3.66 (q, J = 6.4 Hz, 1H), 2.43-2.39 (m, 4H),1.41 (d, J = Hz, 3H). 469

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 9.41 (d, J = 6.0 Hz, 1H), 8.58 (d,J = 2.8 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.14- 8.12 (m, 1H), 8.05 (s,1H), 7.62 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 3.69 (q, J = 6.8 Hz, 1H),3.35-3.30 (m, 4H), 2.67-2.61 (m, 4H), 1.43 (s, 3H). 470

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (d, J = 2.8 Hz, 1H),8.39 (d, J = 1.6 Hz, 1H), 7.62-7.60 (m, 1H), 7.16 (d, J = 7.6 Hz, 1H),6.78 (d, J = 7.6 Hz, 1H), 6.74 (s, 1H), 4.51 (t, J = 8.8 Hz, 2H),3.39-3.37 (m, 1H), 3.33-3.29 (m, 7H), 3.14 (t, J = 8.4 Hz, 2H), 2.57-2.55 (m, 2H), 2.50-2.44 (m, 2H), 1.30 (d, J = 6.8 Hz, 3H). 471

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 12.02 (s, 1H), 7.11 (d, J = 7.2 Hz,1H), 6.74 (d, J = 7.2 Hz, 1H), 6.67 (s, 1H), 4.89 (t, J = 6.0 Hz, 1H),3.38-3.24 (m, 6H), 2.74 (q, J = 7.6 Hz, 1H), 2.43- 2.40 (m, 4H), 2.10(s, 3H), 1.38 (t, J = 2.0 Hz, 3H), 1.26 (t, J = 6.8 Hz, 3H). 472

Racemic ¹H NMR (400 MHz, DMSO-d₆): δ 8.58 (d, J = 2.8 Hz, 1H), 7.70 (s,1H), 7.11 (d, J = 7.6 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.68 (s, 1H),4.88 (q, J = 8.0 Hz, 1H), 3.80-3.79 (m, 4H), 3.38- 3.23 (m, 4H),2.80-2.71 (m, 3H), 2.51-2.37 (m, 4H), 1.38 (t, J = 2.8 Hz, 3H), 1.27 (d,J = 6.4 Hz, 3H). 473

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 9.40 (s, 1H), 8.12 (d, J =8.4 Hz, 1H), 8.04 (s, 1H), 7.82 (d, J = 9.2 Hz, 1H), 7.51 (t, J = 7.6Hz, 1H), 7.24 (d, J = 10 Hz, 1H), 3.86 (s, 3H), 3.75-3.72 (m, 4H),3.70-3.68 (m, 1H), 2.61-2.55 (m, 2H), 2.48-2.45 (m, 2H), 1.42 (d, J =6.8 Hz, 3H) 474

Chiral HPLC SFC Method F: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 12.03 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.6Hz, 1H), 6.68 (s, 1H), 4.89 (q, J = 6.4 Hz, 1H), 3.40-3.24 (m, 5H),2.77-2.68 (m, 1H), 2.44-2.39 (m, 7H), 2.10 (s, 3H), 1.39 (d, J = 6.0 Hz,3H), 1.27 (t, J = 6.40 Hz, 3H). 475

Chiral HPLC SFC Method F: 2nd eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 12.03 (s, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.75 (d, J = 7.6Hz, 1H), 6.68 (s, 1H), 4.90 (q, J = 8.0 Hz, 1H), 3.40-3.24 (m, 5H),2.77-2.68 (m, 1H), 2.42- 2.34 (m, 4H), 2.09 (s, 3H), 1.38 (d, J = 6.0Hz, 3H), 1.27 (t, J = 6.8 Hz, 3H). 476

Chiral HPLC SFC Method F: 1st eluting compound ¹H NMR (400 MHz,DMSO-d₆): δ 8.58 (s, 1H), 7.69 (s, 1H), 7.11 (d, J = 7.6 Hz, 1H), 6.74(d, J = 7.6 Hz, 1H), 6.68 (d, J = Hz, 1H), 4.89 (q, J = 7.2 Hz, 1H),3.80-3.78 (m, 4H), 3.37-3.33 (m, 3H), 2.80-2.77 (m, 3H), 2.37- 2.34 (m,4H), 1.37 (d, J = 6.4 Hz, 3H), 1.28 (d, J = 6.40 Hz, 3H). 477

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 8.14-8.12 (m,2H), 8.04 (s, 1H), 7.81 (d, J = 9.6 Hz, 1H), 7.52- 7.50 (m, 2H), 7.28(d, J = 9.6 Hz, 1H), 3.70-3.3.68 (m, 5H), 2.51-2.50 (m, 4H), 1.41 (d, J= 6.8 Hz, 3H). 478

S- enantiomer ¹H NMR (400 MHz, DMSO-d₆): δ 9.38 (s, 1H), 8.62 (s, 1H),8.32 (s, 1H), 8.12 (d, J = 8.0 Hz, 1H), 8.03 (s, 1H), 8.51 (d, J = 8.0Hz, 1H), 3.80 (s, 3H), 3.73-3.3.68 (m, 5H), 2.57-2.43 (m, 4H), 1.41 (d,J = 6.8 Hz, 3H).

Example B01: Human O-GlcNAcase enzyme inhibition assay

5 μl of the appropriate concentration of a solution of inhibitor inMcIlvaine's Buffer (pH 6.5) in 2% DMSO (for a dose response curvecalculation) is added into each well of a 384-well plate (Greiner,781900). Then, 20 nM of His-Tagged hOGA and 10 μM of FL-GlcNAc(Fluorescein mono-beta-D-(2-deoxy-2-N-acetyl) glucopyranoside; MarkerGene Technologies Inc, M1485) were added to the 384-well plate for afinal volume of 20 μl. After incubation for 60 min at room temperature,the reaction was terminated by the addition of 10 μL of stop buffer (200mM glycine, pH 10.75). The level of fluorescence (λ_(exc) 485 nm;(λ_(emm) 520 nm) was read on a PHERAstar machine. The amount offluorescence measured was plotted against the concentration of inhibitorto produce a sigmoidal dose response curve to calculate an IC₅₀. Allindividual data was corrected by subtraction of the background (Thiamet3 uM=100% inhibition) whilst 0.5% DMSO was considered as the controlvalue (no inhibition).

Example B02: Pharmacodynamic Model: Total protein O-GlcNAcylationimmunoassay (RL2 mAb, Meso Scale electrochemiluminescence (ECL) assay)

The test compound was administered orally to C57BL/6J mice. At definedtime intervals after compound administration, typically a time rangingbetween 2 and 48 hours, preferably between 4 and 24 hours, mice weresacrificed by decapitation for blood collection and forebraindissection. Right brain hemispheres were placed in 2 ml Precellys tubes,snap frozen in dry ice and stored at -80° C. Left hemispheres wereplaced in 2 ml Eppendorf tubes, snap frozen in dry ice and stored at-80° C. until further processing. Blood samples were collected inSarstedt tubes containing 35 IU of Heparin and kept at 4° C. Aftercentrifugation for 10 min at 3800×g, 4° C., 50 μL of plasma from eachsample was transferred to a 1.5 ml Eppendorf tube and stored at −80° C.

For the preparation of soluble brain protein for the immunoassay thehemispheres were homogenized in ice-cold Cytobuster reagent (71009—MerckMillipore) buffer with protease inhibitor cocktail. After centrifugationfor 15 min at 17000×g at 4° C. the supernatants were transferred intopolycarbonate tubes (1 ml). The supernatants were cleared bycentrifugation for 1 h. at 100000×g, 4° C., and the proteinconcentrations were determined by using the BCA kit (23227—Pierce,Rockford, Ill.) according to the manufacturer's instructions.

Total protein O-GlcNAcylation immunoassay:

Samples were randomised and 120 μg/ml (25 μl/well) of soluble brainprotein was directly coated on a Multi-array 96-well high bind plate(L15XB-3 High bind—Meso Scale Discovery) overnight at 4° C. Afterwashing (3× with PBS-T buffer), the plate was blocked with MSD blocker Asolution for 1 h. at room temperature (RT) under agitation. Afterwashing (3× with PBS-T buffer), the plate was incubated with 0.1 μg/mlof a mouse monoclonal antibody directed against O-GlcNAc moieties (RL2;MA1-072—Thermo Scientific) for 1 h. at RT under agitation. For the ECLassay, after washing (3× with PBS-T buffer), 1 μg/ml of a SULFO-TAG™labeled anti-mouse secondary antibody (Meso Scale Discovery) was addedand the plate was incubated for 1 h. at RT under agitation and protectedfrom light. After washing (3× with PBS-T buffer), 150 μl/well of 1× ReadBuffer T was added to the plates before reading on a Sector Imager 6000(Meso Scale Discovery).

Example B03: Pharmaceutical preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bi-distilled water was adjusted to pH 6.5 using 2 N hydrochloricacid, sterile filtered, transferred into injection vials, lyophilizedunder sterile conditions and sealed under sterile conditions. Eachinjection vial contained 5 mg of active ingredient.(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention was melted with 100 g of soy lecithin and 1400 g ofcocoa butter, poured into moulds and allowed to cool. Each suppositorycontained 20 mg of active ingredient.(C) Solution: A solution was prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2H₂O, 28.48 g ofNa₂HPO₄.12H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbi-distilled water. The pH was adjusted to 6.8, and the solution wasmade up to 1 l and sterilized by irradiation. This solution could beused in the form of eye drops.(D) Ointment: 500 mg of an active ingredient according to the inventionwere mixed with 99.5 g of Vaseline under aseptic conditions.(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate was pressed to give tablets in aconventional manner in such a way that each tablet contained 10 mg ofactive ingredient.(F) Coated tablets: Tablets were pressed analogously to EXAMPLE E andsubsequently coated in a conventional manner with a coating of sucrose,potato starch, talc, tragacanth and dye.(G) Capsules: 2 kg of an active ingredient according to the inventionwere introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contained 20 mg of the active ingredient.(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 60 l of bi-distilled water was sterile filtered,transferred into ampoules, lyophilized under sterile conditions andsealed under sterile conditions. Each ampoule contained 10 mg of activeingredient.(I) Inhalation spray: 14 g of an active ingredient according to theinvention were dissolved in 10 l of isotonic NaCl solution, and thesolution was transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponded to a dose of about 0.14mg.

1. A compound of formula (I)

wherein R is straight chain or branched alkyl having 1 to 6 carbonatoms, wherein 1 to 5 hydrogen atoms may be replaced by Hal or OH; W isCH or N; A denotes one of the following groups:

X is N or CR′″; X¹, X² is N or Cr′″; X³ is N or CR′″″; X⁴ is N or CR⁹;R⁹ denotes Hal, NR³R⁴, CHR³R⁴, OR³, CN, straight chain or branched alkylhaving 1 to 12 carbon atoms, wherein 1 to 3 CH₂-groups may be replacedby a group selected from O, NR³, S, SO, SO₂, S(O)(NH),CO, COO, OCO,CONR³, NR³CO and wherein 1 to 5 hydrogen atoms may be replaced by Hal,NR³R⁴ or NO₂; Y is O, S, SO or SO₂; R′, R″ denote each independently H,Hal or straight chain or branched alkyl having 1 to 12 carbon atoms;R′″, R″″ independently denote H, Hal, NR³R⁴, CHR³R⁴, OR³, CN, straightchain or branched alkyl having 1 to 12 carbon atoms, wherein 1 to 3CH₂-groups may be replaced by a group selected from O, NR³, S, SO, SO₂,S(O)(NH), CO, COO, OCO, CONR³, NR³CO and wherein 1 to 5 hydrogen atomsmay be replaced by Hal, NR³R⁴ or NO₂; R′″″ denotes H, Hal, NR³R⁴,CHR³R⁴, CN, straight chain or branched alkyl having 1 to 12 carbonatoms, wherein 1 to 3 CH₂-groups may be replaced by a group selectedfrom O, NR³, S, SO, SO₂, S(O)(NH),CO, COO, OCO, CONR³, NR³CO and wherein1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴ or NO₂; R³, R⁴denote each independently H or a straight chain or branched alkyl grouphaving 1 to 12 carbon atoms; Q denotes one of the following groups:

Z² denotes CR⁵, CR⁶ or N; Z⁴ is N, CH, CON, COCH; Z⁵ is S, O, NR⁸, SO₂,CHR⁵; Z^(5′) is S, O, NR^(B), SO₂; Z⁶ is CH₂, CO; s denotes 0 or 1; T isN, CH or CR⁷; R^(3′) denotes H or a straight chain or branched alkylgroup having 1 to 12 carbon atoms, wherein 1 to 3 CH₂-groups may bereplaced by a group selected from SO₂, CO, O and wherein 1 to 5 hydrogenatoms may be replaced by Hal; R^(3″) denotes a straight chain orbranched alkyl group having 1 to 12 carbon atoms, wherein 1 to 3CH₂-groups are replaced by a group selected from SO₂, CO, O and wherein1 to 5 hydrogen atoms may be replaced by Hal; R⁵, R⁶, R⁷ independentlydenote H, Hal, NR³R⁴, NO₂, straight chain or branched alkyl having 1 to12 carbon atoms, wherein 1 to 3 CH₂-groups may be replaced by a groupselected from O, NR³, S, SO, SO₂, S(O)(NH), CO, COO, OCO, CONR³, NR³COand wherein 1 to 5 hydrogen atoms may be replaced by Hal, NR³R⁴, NO₂,OR³, Het, Ar, Cyc, or denote Ar, Het or Cyc; R⁸ denotes H, methyl orstraight chain or branched alkyl having 2 to 12 carbon atoms, wherein 1to 3 CH₂-groups may be replaced by a group selected from O, NR³, S, SO,SO₂, CO, COO, OCO, CONR³, NR³CO and wherein 1 to 5 hydrogen atoms may bereplaced by Hal, NR³R⁴ or NO₂; Hal denotes F, Cl, Br or I; Het denotes asaturated, unsaturated or aromatic ring, being monocyclic or bicyclic orfused-bicyclic and having 3- to 8-members and containing 1 to 4heteroatoms selected from N, O and S, which may be substituted by 1 to 3substituents selected from R⁵, Hal and OR³; Ar denotes a 6-memberedcarbocyclic aromatic ring or a fused or non fused bicylic aromatic ringsystem, which is optionally substituted by 1 to 3 substituentsindependently selected from R⁵, OR³ and Hal; Cyc denotes a saturated oran unsaturated carbocyclic ring having from 3 to 8 carbon atoms which isoptionally substituted by 1 to 3 substituents independently selectedfrom R⁵ or Hal or OH; m and n denote independently from one another 0,1, 2 or 3 and pharmaceutically usable derivatives, solvates, salts,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios and compounds of formula I, wherein oneor more H atoms are replaced by D (deuterium).
 2. A compound chosen fromthe group consisting of formula Ia and Ib:

wherein A, R, W, Q, n and m have the meaning given in claim
 1. 3. Amixture comprising compounds Ia and Ib according to claim 2, havingidentical groups A, R, W, Q, n and m, in equal or unequal amounts.
 4. Acompound of formula I according to claim 1, wherein R is methyl and/or Wis N.
 5. A compound of formula I according to claim 1, wherein A denotesone of the following groups:

wherein R′ and R″ have the meaning given in claim
 1. 6. A compound offormula I according to claim 1, wherein Q denotes one of the followinggroups:

wherein R^(3′), R⁷ and R⁸ have the meaning given in claim
 1. 7. Acompound of formula I according to claim 1 to claim 6, wherein R⁵, R⁶,R⁷ are independently H, Hal, NR₃R₄, NH₂, N(CH₃)₂, phenyl, 2-,3- or4-hydroxy or methoxyphenyl, alkyl, CF₃, alkoxy (Oalkyl), hydroxyalkylen,alkoxyalkylen, COOH, COOalkyl, CONHalkyl, CONH₂, CON(CH₃)₂, NHCOalkyl,NHalkyl, CO—N-morpholinyl, CON(CH₃)CH₂CH₂N(CH₃)₂, CO-1-piperidinyl,CO-4-hydroxy-1-piperidinyl, CO-1-piperazinyl, CO-4-methyl-1-piperazinyl,CH₂—N-morpholinyl, CH₂N(H)COCH₃, CH₂N(CH₃)COCH₃, substituted orunsubstituted Cyc or Het
 8. A compound of formula I according to any oneof claim 1 to claim 7, wherein m and n simultaneously denote
 1. 9. Acompound according to claim 1, selected from the following group:Configuration No Structure specification  1

racemic  2

racemic  3

racemic  4

racemic 135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

214

215

216

217

231

S-enantiomer 232

S-enantiomer 233

S-enantiomer 234

S-enantiomer 235

S-enantiomer 236

S-enantiomer 237

S-enantiomer 238

S-enantiomer 239

S-enantiomer 240

S-enantiomer 241

S-enantiomer 242

S-enantiomer 243

S-enantiomer 244

S-enantiomer 245

S-enantiomer 246

S-enantiomer 247

S-enantiomer 248

S-enantiomer 249

S-enantiomer 250

S-enantiomer 251

S-enantiomer 252

S-enantiomer 253

S-enantiomer 254

S-enantiomer 255

S-enantiomer 256

S-enantiomer 257

S-enantiomer 258

S-enantiomer 259

S-enantiomer 260

S-enantiomer 261

S-enantiomer 262

S-enantiomer 263

S-enantiomer 264

S-enantiomer 265

S-enantiomer 266

S-enantiomer 267

S-enantiomer 268

S-enantiomer 269

S-enantiomer 270

S-enantiomer 271

S-enantiomer 272

S-enantiomer 273

S-enantiomer 274

S-enantiomer 275

S-enantiomer 276

S-enantiomer 277

S-enantiomer 278

S-enantiomer 279

S-enantiomer 280

S-enantiomer 281

S-enantiomer 282

S-enantiomer 283

S-enantiomer 284

S-enantiomer 285

S-enantiomer 286

S-enantiomer 287

S-enantiomer

and/or and pharmaceutically usable derivatives, solvates, salts,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios.
 10. A compound of formula (I) accordingto any one of claims 1 to 9 for use as a medicament.
 11. A compound offormula (I) according to any one of claims 1 to 9 and pharmaceuticallyusable derivatives, solvates, salts, tautomers, enantiomers, racematesand stereoisomers thereof, including mixtures thereof in all ratios foruse in a treatment of a condition selected from neurodegenerativediseases, diabetes, cancer, cardiovascular diseases and stroke.
 12. Acompound for use in a treatment of a condition according to claim 11,wherein the condition is selected from the group of one or moretauopathies and Alzheimer's disease, Dementia, Amyotrophic lateralsclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment(ALSci), Argyrophilic grain disease, Behavioural variant frontomeporaldmenetia (BvFTD), Bluit disease, Chronic traumatic encephalopathy,Corticobasal degeneration (CBP), Dementia pugilistica, Diffuseneurofibrillary tangles with calcification, Down's syndrome, FamilialBritish dementia, Familial Danish dementia, Frontotemporal dementia withparkinsonism linked to chromosome 17 (FTDP-17), Frontotemporal lobardegeneration (FTLD), Ganglioglioma, Gangliocytoma,Gerstmann-Straussler-Scheinker disease, Globular glia tauopathy,Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegenerationwith brain iron accumulation type 1), Lead encephalopathy,Lipofuscinosis, Meningioangiomatosis, Multiple system atrophy, Myotonicdystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigraldegeneration, Parkinsonism-dementia complex of Guam, Pick's disease(PiD), Parkinson's disease dementia, Postencephalitic parkinsonism(PEP), Primary progressive aphasia, Prion diseases (includingCreutzfeldt-Jakob Disease (GJD), Progressive nonfluent aphasia, VariantCreutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, Kuru,Progressive supercortical gliosis, Progressive supranuclear palsy (PSP),Semantic dementia, Steele-Richardson-Olszewski syndrome, Subacutesclerosing panencephalitis, Tangle-only dementia, Tuberous sclerosis,Huntington's disease and Parkinson's disease, preferably one or moretauopathies and Alzheimer's disease.
 13. A method for treating atauopathy, wherein a compound defined in any one of claims 1 to 9 isadministered to a mammal in need of such treatment.
 14. A method forinhibiting a glycosidase, wherein a system expressing the glycosidase iscontacted with a compound as defined in any one of claims 1 to 9 underin-vitro conditions such that the glycosidase is inhibited.
 15. Apharmaceutical composition comprising as active ingredient a compoundaccording to any one of claims 1 to 9 together with pharmaceuticallytolerable adjuvants and/or excipients, optionally in combination withone or more further active ingredients.